Nijmegen, Netherlands
Nijmegen, Netherlands

Radboud University Nijmegen is a public university with a strong focus on research located in Nijmegen, the Netherlands. Established since 17-10-1923 and situated in the oldest city of the Netherlands, it has seven faculties and enrolls over 19,130 students. Radboud was internationally ranked by QS World University Rankings, and placed at 136th. Wikipedia.

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Radboud University Nijmegen | Date: 2016-11-17

The present invention provides proteins/genes, which are essential for survival, and consequently, for virulence of Streptococcus pneumoniae in vivo, and thus are ideal vaccine candidates for a vaccine preparation against pneumococcal infection. Further, also antibodies against said protein(s) are included in the invention.

Wiering M.,Radboud University Nijmegen | Winnubst M.,University Utrecht
Environmental Science and Policy | Year: 2017

The governance of flood risks varies considerably in different parts of the world. Obviously this is due to the nature and characteristics of flood risks, but in part governance approaches vary because of political differences in the nature of governance itself. What is ‘appropriate’ in this respect depends partly on the prevailing conceptions of the public interest in a country. By applying Alexander's (2002) categorization of public interest to flood risk management practices in The Netherlands, we show that the strongly unitary conception of the public interest (a historic ‘flood risk safety for all’), is intertwined with a state-based, sector-based, hydro-technical governance and expertise system. Although this conception is very strong it is no longer self-evident. Because of changing conceptions of governance in general and because of the felt necessity to adapt to climate change, Dutch flood risk management is gradually changing. Increasingly, the Dutch government has to deal with more dialogical and utilitarian approaches to public interest in the governance of flood risks. The Dutch approach is rooted in community-based interests in flood protection and was centralized and rationalized during the 19th and 20th century. The current flood risk standards are based upon a coarse utilitarian benefit-cost analysis, but evolved into mostly a unitary idea of national safety materialized in law by statutory flood risk standards. The findings show that this unitary concept and status of the public interest of flood risk safety has not diminished; it must, however, increasingly take into account the importance of both processes of decision making (dialogues, deliberations) and neighboring public interests. We conclude that the Dutch conception of the public interest on flood safety is still strong but nevertheless gradually changing, not the least because of a general availability of the information and technology to calculate and differentiate risks. © 2017 The Authors

van der Meer J.W.M.,Radboud University Nijmegen | Simon A.,Radboud University Nijmegen
Rheumatology (United Kingdom) | Year: 2016

Autoinflammatory syndromes are disorders with an exaggerated inflammatory response, mostly in the absence of an appropriate trigger. Prototypic autoinflammatory syndromes are FMF, hyper-IgD syndrome (also known as mevalonate kinase deficiency), TNF receptor-associated periodic syndrome and cryopyrinassociated periodic syndrome. The clinical phenotypes partly overlap (with fever and acute phase response), but also differ between the various syndromes (e.g. regarding fever pattern, episodic vs chronic inflammation and accompanying clinical signs). In recent years, the genetic basis of quite a number of these relatively rare and mostly hereditary disorders has been elucidated. These genetic defects lead to either enhanced production of inflammatory mediators or to a lack of inhibition of these components of the innate immune system. Among these dysregulated inflammatory mediators, the pro-inflammatory cytokine IL-1β stands out. Hence, targeted treatment with blockers of IL-1 action, such as recombinant IL-1 receptor antagonist (IL-1Ra, anakinra) and mAb against IL-1β has met with impressive clinical results. In this article, hyper-IgD syndrome is discussed in more detail, based on 30 years of experience with this syndrome. © The Author 2016.

Haerkens M.H.T.M.,Radboud University Nijmegen
European Journal of Emergency Medicine | Year: 2017

OBJECTIVE: Human factors account for the majority of adverse events. Human factors awareness training entitled Crew Resource Management (CRM) is associated with improved safety and reduced complications and mortality in critically ill patients. We determined the effects of CRM implementation in the trauma room of an Emergency Department (ED). PATIENTS AND METHODS: A prospective 3-year cohort study was carried out in a level 1 ED, admitting more than 12 000 patients annually (>1500 trauma related). At the end of the baseline year, CRM training was performed, followed by an implementation year. The third year was defined as the clinical effect year. The primary outcomes were safety climate, measured using the Safety Attitudes Questionnaire, and ED length of stay. The secondary outcome measures were hospital length of stay and 48-h crude mortality of trauma patients. RESULTS: All 5070 trauma patients admitted to the ED during the study period were included. Following CRM implementation, safety climate improved significantly in three out of six Safety Attitudes Questionnaire domains, both at the end of the implementation and clinical effect years: teamwork climate, safety climate, and stress recognition. ED length of stay of these patients increased from 141 (102–192) in the baseline year to 161 (116–211) and 170 (128–223) min in the implementation and clinical effect years, respectively (P<0.05 vs. baseline). Hospital length of stay was prolonged by 1 day in the implementation and clinical effect years (P<0.05 vs. baseline), whereas mortality was unaltered. CONCLUSION: Although CRM implementation in the ED was associated with an improved safety climate, the time spent by trauma patients in the ED increased. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Geltink G.,Radboud University Nijmegen
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2017

In this paper, we focus on the design of a novel authentication protocol that preserves the privacy of embedded devices. A Physically Unclonable Function (PUF) generates challenge-response pairs that form the source of authenticity between a server and multiple devices. We rely on Authenticated Encryption (AE) for confidentiality, integrity and authenticity of the messages. A challenge updating mechanism combined with an authenticate-before-identify strategy is used to provide privacy. The major advantage of the proposed method is that no shared secrets need to be stored into the device’s non-volatile memory. We design a protocol that supports server authenticity, device authenticity, device privacy, and memory disclosure. Following, we prove that the protocol is secure, and forward and backward privacy-preserving via game transformations. Moreover, a proof of concept is presented that uses a 3-1 Double Arbiter PUF, a concatenation of repetition and BCH error-correcting codes, and the AE-scheme Ketje. We show that our device implementation utilizes 8,305 LUTs on a 28 nm Xilinx Zynq XC7Z020 System on Chip (SoC) and takes only 0.63 ms to perform an authentication operation. © Springer International Publishing AG 2017.

Volokitin S.,Riscure B.V. | Poll E.,Radboud University Nijmegen
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2017

The Java Card platform provides programmers with API classes that act as containers for cryptographic keys and PIN codes. This paper presents a first systematic evaluation of the security that these containers provide against logical attacks, for a number of cards from different manufacturers. Most cards we investigated do not appear to implement any integrity and confidentiality protection for these containers. For the cards that do, this paper presents new logical attacks that bypass these security measures. In particular, we show that the encryption of keys and PINs by the platform can be defeated using decryption functionality that the platform itself offers, so that logical attacks can still retrieve plaintext keys and PINs. We also investigate the possibilities for type confusion to access the global APDU buffer and the presence of undocumented bytecode instructions. © Springer International Publishing AG 2017.

Pous D.,University of Lyon | Rot J.,Radboud University Nijmegen
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2017

In the context of abstract coinduction in complete lattices, the notion of compatible function makes it possible to introduce enhancements of the coinduction proof principle. The largest compatible function, called the companion, subsumes most enhancements and has been proved to enjoy many good properties. Here we move to universal coalgebra, where the corresponding notion is that of a final distributive law. We show that when it exists the final distributive law is a monad, and that it coincides with the codensity monad of the final sequence of the given functor. On sets, we moreover characterise this codensity monad using a new abstract notion of causality. In particular, we recover the fact that on streams, the functions definable by a distributive law or GSOS specification are precisely the causal functions. Going back to enhancements of the coinductive proof principle, we finally obtain that any causal function gives rise to a valid up-to-context technique. © Springer-Verlag GmbH Germany 2017.

Roelofs K.,Radboud University Nijmegen
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2017

Upon increasing levels of threat, animals activate qualitatively different defensive modes, including freezing and active fight-or-flight reactions. Whereas freezing is a form of behavioural inhibition accompanied by parasympathetically dominated heart rate deceleration, fight-or-flight reactions are associated with sympathetically driven heart rate acceleration. Despite the potential relevance of freezing for human stress-coping, its phenomenology and neurobiological underpinnings remain largely unexplored in humans. Studies in rodents have shown that freezing depends on amygdala projections to the brainstem (periaqueductal grey). Recent neuroimaging studies in humans have indicated that similar brain regions may be involved in human freezing. In addition, flexibly shifting between freezing and active defensive modes is critical for adequate stress-coping and relies on fronto-amygdala connections. This review paper presents a model detailing these neural mechanisms involved in freezing and the shift to fight-or-flight action. Freezing is not a passive state but rather a parasympathetic brake on the motor system, relevant to perception and action preparation. Study of these defensive responses in humans may advance insights into human stress-related psychopathologies characterized by rigidity in behavioural stress reactions. The paper therefore concludes with a research agenda to stimulate translational animal–human research in this emerging field of human defensive stress responses. © 2017 The Authors.

Reijnders K.J.A.,Radboud University Nijmegen | Katsnelson M.I.,Radboud University Nijmegen
Physical Review B - Condensed Matter and Materials Physics | Year: 2017

We study Veselago lensing of massless Dirac fermions by n-p junctions for electron sources with a certain polarization. This polarization corresponds to pseudospin for graphene and to real spin for topological insulators. Both for a point source and for injection into a sample through a narrow lead, we find that polarization leads to spatial symmetry breaking. For the Green's function, this results in a vertical displacement, or even complete vanishing of the main focus, depending on the exact polarization. For injection through a lead, it leads to a difference between the amounts of current emitted with positive and negative transversal momenta. We study both systems in detail using the semiclassical approximation. By comparing the results to the exact solutions, we establish that semiclassical methods provide a very effective way to study these systems. For the Green's function, we derive an easy-to-use analytical formula for the vertical displacement of the main focus. For current injection through a lead, we use semiclassical methods to identify two different scattering regimes. © 2017 American Physical Society.

Harren F.J.M.,Radboud University Nijmegen
2016 Conference on Lasers and Electro-Optics, CLEO 2016 | Year: 2016

Mid-infrared OPO and QCL-based spectroscopy will be discussed, together with their applications in the medical field. Also, recent developments in OPO-based dual frequency comb Fourier Transform spectroscopy in this field will be presented. © 2016 OSA.

Shah P.,Cornell University | Wolf K.,Radboud University Nijmegen | Lammerding J.,Cornell University
Trends in Cell Biology | Year: 2017

The nuclear envelope safeguards the genetic material inside the nucleus by separating it from the cytoplasm. Until recently, it was assumed that nuclear envelope (NE) breakdown occurs only in a highly controlled fashion during mitosis when the chromatin is condensed and divided between the daughter cells. However, recent studies have demonstrated that adherent and migrating cells exhibit transient NE rupture during interphase caused by compression from cytoskeletal or external forces. NE rupture results in uncontrolled exchange between the nuclear interior and cytoplasm and leads to DNA damage. In this review, we discuss the causes and consequences of NE rupture, and how NE rupture could contribute to genomic instability. Cells exhibit transient NE rupture during migration through confined spaces and actomyosin-based compression, with the incidence of NE rupture increasing with nuclear confinement.NE rupture is preceded by nuclear membrane blebbing from the nuclear lamina, similar to plasma membrane blebbing at the cell cortex.Nuclear membrane blebbing and NE rupture are driven by intranuclear pressure, resulting from perinuclear actomyosin structures that compress the nucleus. At the same time, perinuclear actin structures associated with Arp2/3 and/or the formin FMN2 may promote nuclear transit through constrictions and prevent NE rupture and DNA damage.NE rupture allows the uncontrolled exchange between nuclear and cytoplasmic content, which, together with mechanical deformation of the nucleus, can lead to chromatin protrusion/fragmentation and DNA damage that promote genomic instability.ESCRT-III proteins mediate NE repair, and inhibiting this machinery along with DNA damage repair pathways reduces cell viability after NE rupture. © 2017 Elsevier Ltd.

Cohen M.X.,Radboud University Nijmegen
International Journal of Psychophysiology | Year: 2017

Cognitive electrophysiology is a subfield of neuroscience that focused on linking M/EEG data to aspects of cognition and the neurophysiological processes that produce them. This field is growing in terms of the novelty and sophistication of findings, data, and data analysis methods. Simultaneously, many areas of modern sciences are experiencing a “replication crisis,” prompting discussions of best practices to produce robust and replicable research. The purpose of this paper is to contribute to this discussion with a particular focus on cognitive electrophysiology. More issues are raised than are answered. Several recommendations are made, including (1) incorporate replications into new experiments, (2) write clear Methods and Results sections, and (3) publish null results. © 2016 Elsevier B.V.

Jacobs R.H.A.H.,Radboud University Nijmegen | Cornelissen F.W.,University of Groningen
Frontiers in Human Neuroscience | Year: 2017

It has been proposed that the top-down guidance of feature-based attention is the basis for the involvement of the amygdala in various tasks requiring emotional decisionmaking (Jacobs et al., 2012a). Aesthetic judgments are correlated with particular visual features and can be considered emotional in nature (Jacobs et al., 2016). Moreover, we have previously shown that various aesthetic judgments result in observers preferentially attending to different visual features (Jacobs et al., 2010). Here, we argue that—together—this explains why the amygdalae become active during aesthetic judgments of visual materials. We discuss potential implications and predictions of this theory that can be tested experimentally. © 2017 Jacobs and Cornelissen.

Schouteten R.,Radboud University Nijmegen
Occupational Medicine | Year: 2017

Background In determining the predictors of occupational health problems, two factors can be distinguished: personal (work ability) factors and work-related factors (burnout, job characteristics). However, these risk factors are hardly ever combined and it is not clear whether burnout or work ability best predicts absenteeism. Aims To relate measures of work ability, burnout and job characteristics to absenteeism as the indicators of occupational health problems. Methods Survey data on work ability, burnout and job characteristics from a Dutch university were related to the absenteeism data from the university's occupational health and safety database in the year following the survey study. The survey contained the Work Ability Index (WAI), Utrecht Burnout Scale (UBOS) and seven job characteristics from the Questionnaire on Experience and Evaluation of Work (QEEW). Results There were 242 employees in the study group. Logistic regression analyses revealed that job characteristics did not predict absenteeism. Exceptional absenteeism was most consistently predicted by the WAI dimensions 'employees' own prognosis of work ability in two years from now' and 'mental resources/vitality' and the burnout dimension 'emotional exhaustion'. Other significant predictors of exceptional absenteeism frequency included estimated work impairment due to diseases (WAI) and feelings of depersonalization or emotional distance from the work (burnout). Conclusions Absenteeism among university personnel was best predicted by a combination of work ability and burnout. As a result, measures to prevent absenteeism and health problems may best be aimed at improving an individual's work ability and/or preventing the occurrence of burnout. © The Author 2016.

Stupakiewicz A.,University of Bialystok | Szerenos K.,University of Bialystok | Afanasiev D.,Radboud University Nijmegen | Kirilyuk A.,Radboud University Nijmegen | Kimel A.V.,Radboud University Nijmegen
Nature | Year: 2017

Discovering ways to control the magnetic state of media with the lowest possible production of heat and at the fastest possible speeds is important in the study of fundamental magnetism, with clear practical potential. In metals, it is possible to switch the magnetization between two stable states (and thus to record magnetic bits) using femtosecond circularly polarized laser pulses. However, the switching mechanisms in these materials are directly related to laser-induced heating close to the Curie temperature. Although several possible routes for achieving all-optical switching in magnetic dielectrics have been discussed, no recording has hitherto been demonstrated. Here we describe ultrafast all-optical photo-magnetic recording in transparent films of the dielectric cobalt-substituted garnet. A single linearly polarized femtosecond laser pulse resonantly pumps specific dâ 'd transitions in the cobalt ions, breaking the degeneracy between metastable magnetic states. By changing the polarization of the laser pulse, we deterministically steer the net magnetization in the garnet, thus writing '0' and '1' magnetic bits at will. This mechanism outperforms existing alternatives in terms of the speed of the write-read magnetic recording event (less than 20 picoseconds) and the unprecedentedly low heat load (less than 6 joules per cubic centimetre). © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Larsen S.S.,Radboud University Nijmegen
Proceedings of the International Astronomical Union | Year: 2015

Dwarf galaxies can have very high globular cluster specific frequencies, and the GCs are in general significantly more metal-poor than the bulk of the field stars. In some dwarfs, such as Fornax, WLM, and IKN, the fraction of metal-poor stars that belong to GCs can be as high as 20%-25%, an order of magnitude higher than the 1%-2% typical of GCs in halos of larger galaxies. Given that chemical abundance anomalies appear to be present also in GCs in dwarf galaxies, this implies severe difficulties for self-enrichment scenarios that require GCs to have lost a large fraction of their initial masses. More generally, the number of metal-poor field stars in these galaxies is today less than what would originally have been present in the form of low-mass clusters if the initial cluster mass function was a power-law extending down to low masses. This may imply that the initial GC mass function in these dwarf galaxies was significantly more top-heavy than typically observed in present-day star forming environments. Copyright © 2017 International Astronomical Union.

Dutreix C.,Radboud University Nijmegen | Katsnelson M.I.,Radboud University Nijmegen
Physical Review B - Condensed Matter and Materials Physics | Year: 2017

This work addresses the one-dimensional problem of Bloch electrons when they are rapidly driven by a homogeneous time-periodic light and linearly coupled to vibrational modes. Starting from a generic time-periodic electron-phonon Hamiltonian, we derive a time-independent effective Hamiltonian that describes the stroboscopic dynamics up to the third order in the high-frequency limit. This yields nonequilibrium corrections to the electron-phonon coupling that are controllable dynamically via the driving strength. This shows in particular that local Holstein interactions in equilibrium are corrected by antisymmetric Peierls interactions out of equilibrium, as well as by phonon-assisted hopping processes that make the dynamical Wannier-Stark localization of Bloch electrons impossible. Subsequently, we revisit the Holstein polaron problem out of equilibrium in terms of effective Green's functions, and specify explicitly how the binding energy and effective mass of the polaron can be controlled dynamically. These tunable properties are reported within the weak- and strong-coupling regimes since both can be visited within the same material when varying the driving strength. This work provides some insight into controllable microscopic mechanisms that may be involved during the multicycle laser irradiations of organic molecular crystals in ultrafast pump-probe experiments, although it should also be suitable for realizations in shaken optical lattices of ultracold atoms. © 2017 American Physical Society.

In 11q23 leukemias, the N-terminal part of the mixed lineage leukemia (MLL) gene is fused to >60 different partner genes. In order to define a core set of MLL rearranged targets, we investigated the genome-wide binding of the MLL-AF9 and MLL-AF4 fusion proteins and associated epigenetic signatures in acute myeloid leukemia (AML) cell lines THP-1 and MV4-11. We uncovered both common as well as specific MLL-AF9 and MLL-AF4 target genes, which were all marked by H3K79me2, H3K27ac and H3K4me3. Apart from promoter binding, we also identified MLL-AF9 and MLL-AF4 binding at specific subsets of non-overlapping active distal regulatory elements. Despite this differential enhancer binding, MLL-AF9 and MLL-AF4 still direct a common gene program, which represents part of the RUNX1 gene program and constitutes of CD34+ and monocyte-specific genes. Comparing these data sets identified several zinc finger transcription factors (TFs) as potential MLL-AF9 co-regulators. Together, these results suggest that MLL fusions collaborate with specific subsets of TFs to deregulate the RUNX1 gene program in 11q23 AMLs.Oncogene advance online publication, 23 January 2017; doi:10.1038/onc.2016.488. © 2017 The Author(s)

Braam E.A.,Radboud University Nijmegen
Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG | Year: 2016

Pulmonary arterial hypertension is a progressive life-threatening disease characterized by vascular remodeling. There is evidence that varied immune mechanism play an important role in progression of pulmonary hypertension.  We describe a case of a 35-year-old woman with idiopathic pulmonary arterial hypertension (IPAH) and a novel BMPR2 mutation, who underwent a successful lung transplantation.  Extensive granulomatous inflammation was seen in the resected lungs. The granulomatous inflammation found in the histology supports  a sarcoid-like reaction due to pulmonary hypertension in the context of the BMPR2 mutation.

Munninghoff J.A.W.,Radboud University Nijmegen | Elemans J.A.A.W.,Radboud University Nijmegen
Chemical Communications | Year: 2017

For more than three decades the scanning tunnelling microscope (STM) has proven to be an indispensable tool to image molecules adsorbed at a surface at the highest detail possible. In addition to simply imaging molecules, STM can also be applied to monitor dynamic surface phenomena, including chemical reactions. By studying reactions at a surface at the single molecule level, unique information about reaction mechanisms can be obtained which remains hidden when conventional ensemble techniques are used. Many STM studies of chemical reactions have been performed in extreme environments like ultrahigh vacuum or high pressure chambers, but these are far removed from conditions in which most chemical and biological processes take place, i.e., in a liquid at ambient atmospheres. This feature paper highlights the developments in the relatively unexplored research area of investigating chemical reactions with an STM at a liquid/solid interface under ambient conditions. Covalent couplings between molecules, light-induced isomerisations, reactions under electrochemical control, and complex multistep processes and catalysis are discussed. © The Royal Society of Chemistry.

Alverdy J.C.,University of Chicago | Hyoju S.K.,University of Chicago | Weigerinck M.,Radboud University Nijmegen | Gilbert J.A.,University of Chicago
British Journal of Surgery | Year: 2017

Background: Since the very early days of surgical practice, surgeons have recognized the importance of considering that intestinal microbes might have a profound influence on recovery from surgical diseases such as appendicitis and peritonitis. Although the pathogenesis of surgical diseases such as cholelithiasis, diverticulosis, peptic ulcer disease and cancer have been viewed as disorders of host biology, they are emerging as diseases highly influenced by their surrounding microbiota. Methods: This is a review of evolving concepts in microbiome sciences across a variety of surgical diseases and disorders, with a focus on disease aetiology and treatment options. Results: The discovery that peptic ulcer disease and, in some instances, gastric cancer can now be considered as infectious diseases means that to advance surgical practice humans need to be viewed as superorganisms, consisting of both host and microbial genes. Applying this line of reasoning to the ever-ageing population of patients demands a more complete understanding of the effects of modern-day stressors on both the host metabolome and microbiome. Conclusion: Despite major advances in perioperative care, surgeons today are witnessing rising infection-related complications following elective surgery. Many of these infections are caused by resistant and virulent micro-organisms that have emerged as a result of human progress, including global travel, antibiotic exposure, crowded urban conditions, and the application of invasive and prolonged medical and surgical treatment. A more complete understanding of the role of the microbiome in surgical disease is warranted to inform the path forward for prevention. © 2017 BJS Society Ltd Published by John Wiley & Sons Ltd

Zwart H.,Radboud University Nijmegen
Life Sciences, Society and Policy | Year: 2017

This paper indicates how continental philosophy may contribute to a diagnostics of contemporary life sciences research, as part of a “diagnostics of the present” (envisioned by continental thinkers, from Hegel up to Foucault). First, I describe (as a “practicing” philosopher) various options for an oblique (or symptomatic) reading of emerging scientific discourse, bent on uncovering the basic “philosophemes” of science (i.e. the guiding ideas, the basic conceptions of nature, life and technology at work in contemporary life sciences research practices). Subsequently, I outline a number of radical transformations occurring both at the object-pole and at the subject-pole of the current knowledge relationship, namely the technification of the object and the anonymisation or collectivisation of the subject, under the sway of automation, ICT and big machines. Finally, I further elaborate the specificity of the oblique perspective with the help of Lacan’s theorem of the four discourses. Philosophical reflections on contemporary life sciences concur neither with a Master’s discourse (which aims to strengthen the legitimacy and credibility of canonical sources), nor with university discourse (which aims to establish professional expertise), nor with what Lacan refers to as hysterical discourse (which aims to challenge representatives of the power establishment), but rather with the discourse of the analyst, listening with evenly-poised attention to the scientific files in order to bring to the fore the cupido sciendi (i.e. the will to know, but also to optimise and to control) which both inspires and disrupts contemporary life sciences discourse. © 2017, The Author(s).

OBJECTIVES: Hereditary pancreatitis (HP) is characterized by recurrent episodes of inflammation of the pancreas. Radiological imaging is used to diagnose HP and to monitor complications. The aim of this study was to describe specific imaging findings in HP. METHODS: We retrospectively collected data of HP patients with serial imaging and reviewed all radiological imaging studies (transabdominal ultrasonography, computed tomography, and magnetic resonance imaging). RESULTS: We included 15 HP patients, with a mean age of 32.5 years (range, 9–61 years) and mean disease duration of 24.1 years (range, 6–42 years). In total, 152 imaging studies were reviewed. Seventy-three percent of patients had a dilated main pancreatic duct (MPD) (width 3.5–18 mm). The MPD varied in size during disease course, with temporary reduction in diameter after drainage procedures. A severe dilated MPD (>10 mm) often coincided with presence of intraductal calcifications (size, 1–12 mm). In 73% of patients, pancreatic parenchyma atrophy occurred, which did not correlate with presence of exocrine or endocrine insufficiency. CONCLUSIONS: In HP, the MPD diameter increases with time, mostly without dilated side branches, and is often accompanied by large intraductal calcifications. The size of the MPD is independent of disease state. Atrophy of pancreatic parenchyma is not correlated with exocrine or endocrine insufficiency. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

The aim of this study was to evaluate the clinical utility of p16/Ki-67 dual staining, for the identification of CIN in high-risk HPV-positive women from a non-responder screening cohort. P16/Ki-67 dual staining, Pap cytology, and HPV16/18 genotyping were performed on physician-taken liquid-based samples from 495 women who tested high-risk HPV positive on self-sampled material (PROHTECT-3B study). Different triage strategies involving p16/Ki-67 dual staining were evaluated for sensitivity, specificity, and predictive value for ≥CIN2 and ≥CIN3, and compared to Pap cytology with a threshold of atypical cells of undetermined significance. Centrally revised histology or an adjusted endpoint with combined high-risk HPV negative and cytology negative follow-up at 6 months was used as gold standard. Pap cytology (threshold atypical cells of undetermined significance) triage of high-risk HPV-positive samples showed a sensitivity of 93% (95% confidence interval: 85–98) with a specificity of 49% (95% confidence interval: 41–56) for ≥CIN3. Three triage strategies with p16/Ki-67 showed a significantly increased specificity with similar sensitivity. P16/Ki-67 triage of all high-risk HPV-positive samples had a sensitivity of 92% (95% confidence interval: 84–97) and a specificity of 61% (95% confidence interval: 54–69) for ≥CIN3. Applying p16/Ki-67 triage to only high-risk HPV-positive women with low-grade Pap cytology showed a similar sensitivity of 92% (95% confidence interval: 84–97), with a specificity for ≥CIN3 of 64% (95% confidence interval: 56–71). For high-risk HPV-positive women with low-grade and normal Pap cytology, triage with p16/Ki-67 showed a sensitivity of 96% (95% confidence interval: 89–99), and a specificity of 58% (95% confidence interval: 50–65). HPV16/18 genotyping combined with Pap cytology showed a sensitivity and specificity for ≥CIN3 similar to Pap cytology with an atypical cells of undetermined significance threshold. Because the quality of Pap cytology worldwide varies, and differences in sensitivity and specificity are limited between the three selected strategies, p16/Ki-67 triage of all high-risk HPV-positive samples would be the most reliable strategy in triage of high-risk HPV-positive women with an increased specificity and similar sensitivity compared with Pap cytology triage.Modern Pathology advance online publication, 17 March 2017; doi:10.1038/modpathol.2017.16. © 2017 United States & Canadian Academy of Pathology USCAP, Inc

Cohen M.X.,Radboud University Nijmegen
eLife | Year: 2017

This paper presents a new framework for analyzing cross-frequency coupling in multichannel electrophysiological recordings. The generalized eigendecomposition-based cross- frequency coupling framework (gedCFC) is inspired by source-separation algorithms combined with dynamics of mesoscopic neurophysiological processes. It is unaffected by factors that confound traditional CFC methods-such as non-stationarities, non-sinusoidality, and non—niform phase angle distributions—attractive properties considering that brain activity is neither stationary nor perfectly sinusoidal. The gedCFC framework opens new opportunities for conceptualizing CFC as network interactions with diverse spatial/topographical distributions. Five specific methods within the gedCFC framework are detailed, these are validated in simulated data and applied in several empirical datasets. gedCFC accurately recovers physiologically plausible CFC patterns embedded in noise that causes traditional CFC methods to perform poorly. The paper also demonstrates that spike-field coherence in multichannel local field potential data can be analyzed using the gedCFC framework, which provides significant advantages over traditional spike-field coherence analyses. Null-hypothesis testing is also discussed. © Cohen.

Hornikx J.,Radboud University Nijmegen | van Meurs F.,Radboud University Nijmegen | Hof R.-J.,Radboud University Nijmegen
Journal of International Consumer Marketing | Year: 2013

Advertising often confronts consumers with foreign languages, such as German or French in the U.S., but little is known about the circumstances under which this is effective. The linguistic theory of foreign-language display claims that the congruence with the product is the essential element in its effectiveness. This study investigates this premise by having Dutch participants (N = 150) evaluate ads for products that were (in)congruent with the language of the slogan (French, German, Spanish). Results show that foreign-language display is indeed more effective for congruent (e.g., wine-French) than for incongruent products (e.g., beer-French). © 2013 Copyright Taylor and Francis Group, LLC.

Ouborg N.J.,Radboud University Nijmegen | Pertoldi C.,University of Aarhus | Loeschcke V.,University of Aarhus | Bijlsma R.K.,University of Groningen | Hedrick P.W.,Arizona State University
Trends in Genetics | Year: 2010

Over the past twenty years conservation genetics has progressed from being mainly a theory-based field of population biology to a full-grown empirical discipline. Technological developments in molecular genetics have led to extensive use of neutral molecular markers such as microsatellites in conservation biology. This has allowed assessment of the impact of genetic drift on genetic variation, of the level of inbreeding within populations, and of the amount of gene flow between or within populations. Recent developments in genomic techniques, including next generation sequencing, whole genome scans and gene-expression pattern analysis, have made it possible to step up from a limited number of neutral markers to genome-wide estimates of functional genetic variation. Here, we focus on how the transition of conservation genetics to conservation genomics leads to insights into the dynamics of selectively important variation and its interaction with environmental conditions, and into the mechanisms behind this interaction. © 2010 Elsevier Ltd.

Aims: To test whether (i) drinking motives predict the frequency of pre-drinking (i.e. alcohol consumption before going out); (ii) drinking motives predict HDGE (heavy drinking on a given evening: 4+ for women, 5+ for men) and related adverse consequences (hangover, injuries, blackouts, etc.), even when pre-drinking is accounted for, and (iii) drinking motives moderate the impact of pre-drinking on HDGE and consequences. Design: Using the internet-based cellphone-optimized assessment technique (ICAT), participants completed a series of cellphone questionnaires every Thursday, Friday and Saturday evening over 5 weeks. Setting: French-speaking Switzerland. Participants: A total of 183 young adults [53% female, mean age (standard deviation)=23.1 (3.1)] who completed 7828 questionnaires on 1441 evenings. Measurements: Drinking motives assessed at baseline, alcohol consumption assessed at 8 p.m., 9 p.m., 10 p.m., 11 p.m. and midnight and consequences assessed at 11 a.m. the next day. Findings: Gender-separate multi-level models revealed that pre-drinking predicted HDGE (men: B=2.17, P<0.001; women: B=2.12, P<0.001) and alcohol-related consequences (men: B=0.24, P<0.01; women: B=0.29, P<0.001). Enhancement motives were found to predict HDGE (B=0.48, P<0.05) and related consequences (B=0.09, P<0.05) among men, while among women coping motives had the same effect (HDGE: B=0.73, P<0.001; consequences: B=0.13, P<0.01). With the exception of conformity motives among women (B=0.54, P<0.05), however, no drinking motive dimension predicted the frequency of pre-drinking, while coping and conformity motives moderated the impact of pre-drinking on HDGE (men, conformity: B=-1.57, P<0.05) and its consequences (men, coping: B=-0.46, P<0.01; women, coping: B=0.76, P<0.05). Conclusions: Among young adults in Switzerland, heavy weekend drinking and the related consequences seem to result from the combination of pre-drinking, level of negative reinforcement drinking for women and positive reinforcement drinking for men. © 2013 Society for the Study of Addiction.

Clark A.R.,Institute of Structural and Molecular Biology | Lubsen N.H.,Radboud University Nijmegen | Slingsby C.,Institute of Structural and Molecular Biology
International Journal of Biochemistry and Cell Biology | Year: 2012

α-Crystallin, a major component of the eye lens cytoplasm, is a large multimer formed from two members of the small heat shock protein (sHsp) family. Inherited crystallin mutations are a common cause of childhood cataract, whereas miscellaneous changes to the long-lived crystallins cause age-related cataract, the most common cause of blindness worldwide. Newly formed eye lens cells use proteostasis to deal with the consequences of mutations, whereas mature lens cells, devoid of the ATP-driven folding and degradation machines, are hypothesized to have the α-crystallin "holdase" chaperone function to prevent protein aggregation. We discuss the impact of truncating and missense mutations on α-crystallin, based on recent progress towards determining sHsp 3D structure. Dominant missense mutations to the "α-crystallin domain" of αA- (HSPB4) or αB-crystallin (HSPB5) occur on residues predicted to facilitate domain dynamics. αB-Crystallin is also expressed in striated muscle and mutations cause myopathy. The impact on these cellular cytoplasms is compared where sHsp multimer partners and metabolic constraints are different. Selected inherited mutations of the lens β- and γ-crystallins are considered in the context of their possible dependence on the "holdase" chaperone function of α-crystallin. Looking at discrete changes to specific crystallin polypeptide chains that can function as chaperone or substrate provide insights into the workings of a cytoplasmic proteostatic system. These observations provide a framework for validating the function of α-crystallin as a chaperone, or as a lens space filler adapted from a chaperone function. Understanding the mechanistic role of α-crystallins will aid progress in research into age-related cataract and adult-onset myopathy. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology.

Ciompi F.,Autonomous University of Barcelona | Ciompi F.,Radboud University Nijmegen
IEEE Transactions on Pattern Analysis and Machine Intelligence | Year: 2014

We analyze sequential image labeling methods that sample the posterior label field in order to gather contextual information. We propose an effective method that extracts local Taylor coefficients from the posterior at different scales. Results show that our proposal outperforms state-of-the-art methods on MSRC-21, CAMVID, eTRIMS8 and KAIST2 data sets. © 1979-2012 IEEE.

Van Gelder M.M.H.J.,Radboud University Nijmegen | De Jong-Van Den Berg L.T.W.,University of Groningen | Roeleveld N.,Radboud University Nijmegen
Human Reproduction | Year: 2014

STUDY QUESTION: What is the current state of knowledge on the human risks of drugs suspected to be associated with teratogenic mechanisms? SUMMARY ANSWER: Evidence for the presence or absence of human risks of birth defects is scarce or non-existent for the majority of drugs associated with teratogenic mechanisms. WHAT IS KNOWN ALREADY: Medical drugs suspected to be associated with teratogenic mechanisms are dispensed to a significant proportion of women in the first trimester of pregnancy. However, an overview of the current state of knowledge on the human teratogenic effects of these drugs is lacking. STUDY DESIGN, SIZE, DURATION: We performed an extensive literature review of studies in the English language which examined the associations between selected drugs and specific birth defects. The literature was identified from MEDLINE and EMBASE from database inception (January 1946 and January 1974, respectively) through December 2012 using 287 terms for the drugs of interest. We only included studies if they specified birth defect subtypes and, specifically for cohort studies, involved live born infants. PARTICIPANTS/ MATERIALS, SETTING, METHODS: Of 14 406 potentially relevant articles, 556 full-text articles were assessed for eligibility and 250 met the inclusion criteria. The studies included were divided into four categories according to their design to increase the validity of our study. MAIN RESULTS AND THE ROLE OF CHANCE: Epidemiologic studies assessing teratogenic risks were identified for less than half of the drugs included in the review. A substantial variation in study design and data collection methods was observed. When the data collection method is of questionable validity, study quality may be affected considerably. For only 15 drugs of interest, birth defects were assessed in at least 1000 infants in cohort studies, and 13 of these were associated with one or more specific birth defects. The majority of associations observed in case-control studies are as yet unconfirmed. For most drugs and drug groups, however, the numbers of exposed infants studied were too small to draw any conclusions regarding their human teratogenic risks. LIMITATIONS, REASONS FOR CAUTION: The validity of our review is limited by the validity and reporting of the studies from which the data were extracted. Some relevant studies might have been missed owing to the exclusion of articles not in the English language and publication bias. WIDER IMPLICATIONS OF THE FINDINGS: It is a cause of concern that the drugs most often dispensed in the first trimester of pregnancy are not necessarily the drugs for which teratogenic risks have been studied. Future studies should focus on those drugs that are most commonly used during pregnancy and for which the teratogenic risks are unknown, such as iron preparations, serotonin receptor agonists or antagonists, drugs used in fertility treatment, dihydrofolate reductase inhibitors. STUDY FUNDING/COMPETING INTEREST(S): Marleen van Gelder was supported by the Netherlands Organisation for Scientific Research/NWO (grant no. 021.001.008). No competing interests are declared.TRIAL REGISTRATION NUMBERN/A. © The Author 2013.

Bojak I.,Radboud University Nijmegen | Liley D.T.J.,Swinburne University of Technology
PLoS Computational Biology | Year: 2010

By modelling the average activity of large neuronal populations, continuum mean field models (MFMs) have become an increasingly important theoretical tool for understanding the emergent activity of cortical tissue. In order to be computationally tractable, long-range propagation of activity in MFMs is often approximated with partial differential equations (PDEs). However, PDE approximations in current use correspond to underlying axonal velocity distributions incompatible with experimental measurements. In order to rectify this deficiency, we here introduce novel propagation PDEs that give rise to smooth unimodal distributions of axonal conduction velocities. We also argue that velocities estimated from fibre diameters in slice and from latency measurements, respectively, relate quite differently to such distributions, a significant point for any phenomenological description. Our PDEs are then successfully fit to fibre diameter data from human corpus callosum and rat subcortical white matter. This allows for the first time to simulate long-range conduction in the mammalian brain with realistic, convenient PDEs. Furthermore, the obtained results suggest that the propagation of activity in rat and human differs significantly beyond mere scaling. The dynamical consequences of our new formulation are investigated in the context of a well known neural field model. On the basis of Turing instability analyses, we conclude that pattern formation is more easily initiated using our more realistic propagator. By increasing characteristic conduction velocities, a smooth transition can occur from self-sustaining bulk oscillations to travelling waves of various wavelengths, which may influence axonal growth during development. Our analytic results are also corroborated numerically using simulations on a large spatial grid. Thus we provide here a comprehensive analysis of empirically constrained activity propagation in the context of MFMs, which will allow more realistic studies of mammalian brain activity in the future. © 2010 Bojak, Liley.

Ten Broek R.P.G.,Radboud University Nijmegen | Bleichrodt R.P.,Radboud University Nijmegen | Van Goor H.,Radboud University Nijmegen
Human Reproduction Update | Year: 2013

Introduction: Adhesion formation is the most common complication following peritoneal surgery and the leading cause of small bowel obstruction, acquired infertility and inadvertent organ injury at reoperation. Using a 'good surgical technique' is advocated as a first step in preventing adhesions. However, the evidence for different surgical techniques to reduce adhesion formation needs confirmation. Methods: Pubmed, Embase and CENTRAL were searched to identify randomized controlled trials that investigated the effect of various aspects of surgical technique on adhesion-related outcomes. Clinical outcomes and incidence of adhesions were the primary endpoints. Identification of papers and data extraction were performed by two independent researchers. Results: There were 28 papers with 27 studies included for a systematic review. Of these, 17 studies were eligible for meta-analysis and 11 for qualitative assessment only. None of the techniques that were compared significantly reduced the incidence of adhesive small bowel obstruction. In a small low-quality trial, the pregnancy rate increased after subserous fixation of suture knots. However, the incidence of adhesions was lower after laparoscopic compared with open surgery [relative risk (RR) 0.14; 95% confidence interval (CI): 0.03-0.61] and when the peritoneum was not closed (RR 0.36; 95% CI: 0.21-0.63). Conclusions: None of the specific techniques that were compared reduced the two main adhesion-related clinical outcomes, small bowel obstruction and infertility. The meta-analysis provides little evidence for the surgical principle that using less invasive techniques, introducing less foreign bodies or causing less ischaemia reduces the extent and severity of adhesions. © The Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

Verbeek D.S.,University of Groningen | Van De Warrenburg B.P.C.,Radboud University Nijmegen
Seminars in Neurology | Year: 2011

The relevant clinical, genetic, and cell biologic aspects of the dominantly inherited spinocerebellar ataxias (SCAs) are reviewed in this article. SCAs are diseases of the entire nervous system; in addition to cerebellar ataxia, the central (but not obligate) disease feature, many noncerebellar complications can be present as well. There are over 35 genetic subtypes: although those caused by expanded CAG repeats are still the more common ones, the majority of the recent SCAs have been caused by more conventional mutations. Genotypephenotype correlations do exist and are most clear for the repeat expansion, where repeat length partially explains age at onset, disease severity and progression, and the core clinical phenotype. Some common themes within the disease mechanisms seem to emerge, including misfolding and aggregation, impairment of the protein quality control system, abnormal protein interactions, disruption of gene transcription, RNA toxicity, and changes in glutamate and calcium signaling. Yet despite this exciting progress in the molecular genetic background and suggested corresponding pathways, there is still no drug available that is specifically designed for or targeted at the mechanisms at play. Copyright © 2011 by Thieme Medical Publishers, Inc.

Chu X.,University of Montana | Groenenboom G.C.,Radboud University Nijmegen
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2013

A minimum at ∼39 eV is observed in the high-harmonic-generation spectra of N2 for several laser intensities and frequencies. This minimum appears to be invariant for different molecular orientations. We reproduce this minimum for a set of laser parameters and orientations in time-dependent density-functional-theory calculations, which also render orientation-dependent maxima at 23-26 eV. Photon energies of these maxima overlap with ionization potentials of excited states observed in photoelectron spectra. Time profile analysis shows that these maxima are caused by resonance-enhanced multiphoton excitation. We propose a four-step mechanism, in which an additional excitation step is added to the well-accepted three-step model. Excitation to a linear combination of Rydberg states c4′1Σu+ and c3 1Πu gives rise to an orientation-invariant minimum analogous to the "Cooper minimum" in argon. When the molecular axis is parallel to the polarization direction of the field, a radial node goes through the atomic centers, and hence the Cooper-like minimum coincides with the minimum predicted by a modified two-center interference model that considers the de-excitation of the ion and symmetry of the Rydberg orbital. © 2013 American Physical Society.

Zedlitz A.M.E.E.,Radboud University Nijmegen | Rietveld T.C.M.,Radboud University Nijmegen | Fasotti L.,Radboud University Nijmegen
Stroke | Year: 2012

Background and Purpose-Fatigue is a common, persistent consequence of stroke, and no evidence-based treatments are currently available to alleviate fatigue. A new treatment combining cognitive therapy (CO) with graded activity training (GRAT), called COGRAT, was developed to alleviate fatigue and fatigue-related symptoms. This study compared the effectiveness of the COGRAT intervention with a CO-only intervention after a 3-month qualification period without intervention. Methods-This randomized, controlled, assessor-blind clinical trial was conducted in 8 rehabilitation centers. Eighty-three stroke patients (>4 months after stroke) were randomly assigned to 12 weeks of CO or COGRAT after qualification. Seventy-three patients completed treatment and 68 were available at follow-up. Primary outcomes (Checklist Individual Strength-subscale Fatigue (CIS-f); self-observation list-fatigue (SOL-f)) and secondary outcomes (Hospital Anxiety and Depression Scale, Stroke-Adapted Sickness Impact Profile, SOL-pain, SOL-sleep-D, 6-minute walk test) were collected at baseline (before and after qualification period) and after treatment (immediate and 6-month follow-up). Results-The qualification period showed stable outcome measures. Both treatments showed significant beneficial effects on fatigue (CIS-f: η 2 p=0.48, P<0.001) and other outcomes (except pain and anxiety) with intention-to-treat analyses. Gains for the COGRAT group exceeded those in the CO group on number of individuals showing clinical improvement on the CIS-f (≥8 points: 58% versus 24%) and on physical endurance (η 2 p=0.20, P<0.001). Conclusions-A 12-week cognitive therapy program can alleviate persistent fatigue after stroke. The best results are obtained when cognitive therapy is augmented with graded activity training. Clinical Trial Registration-URL: Unique identifier: NTR2704. © 2012 2012 American Heart Association, Inc.

Pfukwa R.,Stellenbosch University | Kouwer P.H.J.,Radboud University Nijmegen | Rowan A.E.,Radboud University Nijmegen | Klumperman B.,Stellenbosch University
Angewandte Chemie - International Edition | Year: 2013

A biomimetic approach has been used for the templated self-assembly of a helical poly(para-aryltriazole) foldamer. The solvophobic folding process yields helices that further self-assemble into long nanotubes (see picture; scale bar: 100a nm). Constructs of controlled length and chirality can be generated by applying a poly(γ-benzyl-l-glutamate) scaffold at the appropriate assembly conditions, mimicking tobacco mosaic virus self-assembly. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Molendijk M.L.,Leiden University | Spinhoven P.,Leiden University | Polak M.,Leiden University | Bus B.A.A.,Radboud University Nijmegen | And 4 more authors.
Molecular Psychiatry | Year: 2014

Meta-analyses, published in 2008-2010, have confirmed abnormally low serum brain-derived neurotrophic factor (BDNF) concentrations in depressed patients and normalization of this by antidepressant treatment. These findings are believed to reflect peripheral manifestations of the neurotrophin hypothesis, which states that depression is secondary to an altered expression of BDNF in the brain. Since the publication of these meta-analyses, the field has seen a huge increase in studies on these topics. This motivated us to update the evidence on the aforementioned associations and, in addition, to compile the data on serum BDNF concentrations in relation to the symptom severity of depression. Using a manifold of data as compared with earlier meta-analyses, we find low serum BDNF concentrations in 2384 antidepressant-free depressed patients relative to 2982 healthy controls and to 1249 antidepressant-treated depressed patients (Cohen's d=-0.71 and -0.56, P-values <0.0000001). When publication bias is accounted for, these effect-sizes become substantially smaller (d=-0.47 and -0.34, respectively, P-values<0.0001). We detect between-study heterogeneity in outcomes for which only year of publication and sample size are significant moderators, with more recent papers and larger samples sizes in general being associated with smaller between-group differences. Finally, the aggregated data negate consistent associations between serum BDNF concentrations and the symptom severity of depression. Our findings corroborate the claim that altered serum BDNF concentrations are peripheral manifestations of depression. However, here we highlight that the evidence for this claim is slimmer as was initially thought and amidst a lot of noise. © 2014 Macmillan Publishers Limited All rights reserved.

Chu X.,University of Montana | Groenenboom G.C.,Radboud University Nijmegen
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2012

The observation of the isotope effect in the high-order-harmonic generation (HHG) of H 2 presents a challenge for time-dependent density-functional-theory (TDDFT) methods, since this effect is related to the dynamics of the ion created in the tunneling ionization step of HHG and it depends on the harmonic order. As an initial step toward describing this effect within current computational capacity, we benchmark a method in which the nuclear and electronic degrees of freedom are separated and both treated quantum mechanically. For the electrons two TDDFT formalisms are adopted. Although the ion-dynamics effect is not described in our method, it reproduces the measured D 2-to-H 2 HHG ratios up to the 25th harmonic when the 35th is the classical cutoff. Beyond the 25th harmonic, however, our results show substantial deviation and are sensitive to the laser intensity. A higher intensity reproduces the experimental results. Analysis reveals an R-dependent phase factor as the cause of the isotope effect in our calculation. We isolate this phase factor and propose a strong-field-approximation-phase model, which reproduces experimental data, including those for which the ion-dynamics model has to be further modified. We show that the model that we propose is intrinsically related to the ion-dynamics model. Our model provides a correction to the TDDFT approach when the ion-dynamics effect becomes significant. It also indicates that the isotope effect is not only a probe for the ion created by the external field but is ultimately a more useful probe for the ground-state nuclear wave function. For all molecules whose vertical ionization potential strongly depends on the nuclear geometry, HHG may serve as a sensitive ultrafast probe of nuclear dynamics. © 2012 American Physical Society.

Low T.,IBM | Jiang Y.,Zhejiang Normal University | Jiang Y.,Purdue University | Katsnelson M.,Radboud University Nijmegen | Guinea F.,CSIC - Institute of Materials Science
Nano Letters | Year: 2012

The combination of high-frequency vibrations and metallic transport in graphene makes it a unique material for nanoelectromechanical devices. In this Letter, we show that graphene-based nanoelectromechanical devices are extremely well suited for charge pumping due to the sensitivity of its transport coefficients to perturbations in electrostatic potential and mechanical deformations, with the potential for novel small scale devices with useful applications. © 2012 American Chemical Society.

Rutten-Jacobs L.C.A.,Radboud University Nijmegen | Arntz R.M.,Radboud University Nijmegen | Maaijwee N.A.M.,Radboud University Nijmegen | Schoonderwaldt H.C.,Radboud University Nijmegen | And 3 more authors.
JAMA - Journal of the American Medical Association | Year: 2013

Importance: Long-term data on mortality after first-ever stroke in adults aged 18 through 50 years are scarce and usually restricted to ischemic stroke. Moreover, expected mortality not related to first-ever stroke is not taken in account. Objectives: To investigate long-term mortality and cause of death after acute stroke in adults aged 18 through 50 years and to compare this with nationwide age- and sex-matched mortality rates. Design, Setting, and Participants: The Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation (FUTURE) study, a prospective cohort study of prognosis after transient ischemic attack (TIA), ischemic stroke, or hemorrhagic stroke in adults aged 18 through 50 years admitted to Radboud University Nijmegen Medical Centre, the Netherlands, between January 1, 1980, and November 1, 2010. The survival status of 959 consecutive patients with a first-ever TIA (n=262), ischemic stroke (n=606), or intracerebral hemorrhage (n=91)was assessed as of November 1, 2012.Mean follow-up duration was 11.1 (SD, 8.7) years (median, 8.3 [interquartile range, 4.0-17.4]). Observed mortality was compared with the expected mortality, derived from mortality rates in the general population with similar age, sex, and calendar-year characteristics. Main Outcome Measures: Cumulative 20-year mortality among 30-day survivors of stroke. Results: At the end of follow-up, 192 patients (20.0%) had died. For each stroke type, observed 20-year mortality among 30-day survivors exceeded expected mortality in the general population. For ischemic stroke, cumulative 20-year mortality among 30-day survivors was higher in men than in women (33.7% [95% CI, 26.1%-41.3%] vs 19.8% [95% CI, 13.8%-25.9%]). The standardized mortality ratio was 4.3 (95% CI, 3.2-5.6) for women and 3.6 (95% CI, 2.8-4.6) for men. For all etiologic subtypes of ischemic stroke, observed mortality exceeded expected mortality. Conclusions and Relevance: Among adults aged 18 through 50 years, 20-year mortality following acute stroke was relatively high compared with expected mortality. These findings may warrant further research evaluating secondary prevention strategies in these patients. ©2013 American Medical Association. All rights reserved.

Beijers R.,Radboud University Nijmegen | Buitelaar J.K.,Donders Institute for Brain | Buitelaar J.K.,Karakter Child and Adolescent Psychiatry University Center | de Weerth C.,Radboud University Nijmegen
European Child and Adolescent Psychiatry | Year: 2014

Accumulating evidence from preclinical and clinical studies indicates that maternal psychosocial stress and anxiety during pregnancy adversely affect child outcomes. However, knowledge on the possible mechanisms underlying these relations is limited. In the present paper, we review the most often proposed mechanism, namely that involving the HPA axis and cortisol, as well as other less well-studied but possibly relevant and complementary mechanisms. We present evidence for a role of the following mechanisms: compromised placental functioning, including the 11β-HSD2 enzyme, increased catecholamines, compromised maternal immune system and intestinal microbiota, and altered health behaviors including eating, sleep, and exercise. The roles of (epi)genetics, the postnatal environment and the fetus are also discussed. We conclude that maternal prenatal psychosocial stress is a complex phenomenon that affects maternal emotions, behavior and physiology in many ways, and may influence the physiology and functioning of the fetus through a network of different pathways. The review concludes with recommendations for future research that helps our understanding of the mechanisms by which maternal prenatal stress exerts its effect on the fetus. © 2014, Springer-Verlag Berlin Heidelberg.

Brouwer D.,Netherlands Psychoanalytic Institute | Brouwer D.,University of Twente | Meijer R.R.,University of Groningen | Zevalkink J.,Radboud University Nijmegen
Psychological Assessment | Year: 2013

The Beck Depression Inventory-II (BDI-II; Beck, Steer, & Brown, 1996) is intended to measure severity of depression, and because items represent a broad range of depressive symptoms, some multidimensionality exists. In recent factor-analytic studies, there has been a debate about whether the BDI-II can be considered as one scale or whether subscales should be distinguished. In the present study, we applied a bifactor model to evaluate the extent to which scores reflect a single variable in a large sample of 1,530 clinical outpatients. We found that total scale score variation reflected some multidimensionality, but not enough to justify the scoring of subscales. We conclude that the BDI-II total scale score reflects a single construct and that reporting and interpreting subscale scores may result in misleading conclusions. © 2012 American Psychological Association.

Klooster K.,University of Groningen | Ten Hacken N.H.T.,University of Groningen | Hartman J.E.,University of Groningen | Kerstjens H.A.M.,University of Groningen | And 2 more authors.
New England Journal of Medicine | Year: 2015

BACKGROUND Bronchoscopic lung-volume reduction with the use of one-way endobronchial valves is a potential treatment for patients with severe emphysema. To date, the benefits have been modest but have been hypothesized to be much larger in patients without interlobar collateral ventilation than in those with collateral ventilation. METHODS We randomly assigned patients with severe emphysema and a confirmed absence of collateral ventilation to bronchoscopic endobronchial-valve treatment (EBV group) or to continued standard medical care (control group). Primary outcomes were changes from baseline to 6 months in forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and 6-minute walk distance. RESULTS Eighty-four patients were recruited, of whom 16 were excluded because they had collateral ventilation (13 patients) or because lobar segments were inaccessible to the endobronchial valves (3 patients). The remaining 68 patients (mean [±SD] age, 59±9 years; 46 were women) were randomly assigned to the EBV group (34 patients) or the control group (34). At baseline, the FEV1 and FVC were 29±7% and 77±18% of the predicted values, respectively, and the 6-minute walk distance was 374±86 m. Intention-to-treat analyses showed significantly greater improvements in the EBV group than in the control group from baseline to 6 months: the increase in FEV1 was greater in the EBV group than in the control group by 140 ml (95% confidence interval [CI], 55 to 225), the increase in FVC was greater by 347 ml (95% CI, 107 to 588), and the increase in the 6-minute walk distance was greater by 74 m (95% CI, 47 to 100) (P<0.01 for all comparisons). By 6 months, 23 serious adverse events had been reported in the EBV group, as compared with 5 in the control group (P<0.001). One patient in the EBV group died. Serious treatmentrelated adverse events in this group included pneumothorax (18% of patients) and events requiring valve replacement (12%) or removal (15%). CONCLUSIONS Endobronchial-valve treatment significantly improved pulmonary function and exercise capacity in patients with severe emphysema characterized by an absence of interlobar collateral ventilation. Copyright © 2015 Massachusetts Medical Society. All rights reserved.

Peters R.J.R.W.,Radboud University Nijmegen | Marguet M.,CNRS Organic Polymer Chemistry Laboratory | Marais S.,University of Bordeaux Segalen | Fraaije M.W.,University of Groningen | And 2 more authors.
Angewandte Chemie - International Edition | Year: 2014

Enzyme-filled polystyrene-b-poly(3-(isocyano-L-alanyl-aminoethyl)thiophene) (PS-b-PIAT) nanoreactors are encapsulated together with free enzymes and substrates in a larger polybutadiene-b-poly(ethylene oxide) (PB-b-PEO) polymersome, forming a multicompartmentalized structure, which shows structural resemblance to the cell and its organelles. An original cofactor-dependent three-enzyme cascade reaction is performed, using either compatible or incompatible enzymes, which takes place across multiple compartments. Mimicking cells: Enzyme-filled polystyrene-b-poly(3-(isocyano-L-alanylaminoethyl) thiophene) (PS-b-PIAT) nanoreactors have been encapsulated together with free enzymes and substrates in a larger polymersome to form a multicompartmentalized structure, which shows structural resemblance to a cell and its organelles (see picture). An original cofactor-dependent three-enzyme cascade reaction, with either compatible or incompatible enzymes, takes place across multiple compartments. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Brandtzaeg P.,University of Oslo | Van Deuren M.,Radboud University Nijmegen
Methods in Molecular Biology | Year: 2012

The clinical symptoms induced by Neisseria meningitidis reflect compartmentalized intravascular and intracranial bacterial growth and inflammation. In this chapter, we describe a classification system for meningococcal disease based on the nature of the clinical symptoms. Meningococci invade the subarachnoid space and cause meningitis in as many as 50-70% of patients. The bacteremic phase is moderate in patients with meningitis and mild systemic meningococcemia but graded high in patients with septic shock. Three landmark studies using this classification system and comprising 862 patients showed that 37-49% developed meningitis without shock, 10-18% shock without meningitis, 7-12% shock and meningitis, and 18-33% had mild meningococcemia without shock or meningitis. N. meningitidis lipopolysaccharide (LPS) is the principal trigger of the innate immune system via activation of the Toll-like receptor 4-MD2 cell surface receptor complex on myeloid and nonmyeloid human cells. The intracellular signals are conveyed via MyD88-dependent and-independent pathways altering the expression of >4,600 genes in target cells such as monocytes. However, non-LPS molecules contribute to inflammation, but 10-100-fold higher concentrations are required to reach the same responses as induced by LPS. Activation of the complement and coagulation systems is related to the bacterial load in the circulation and contributes to the development of shock, organ dysfunction, thrombus formation, bleeding, and long-term complications in patients. Despite rapid intervention and advances in patient intensive care, why as many as 30% of patients with systemic meningococcal disease develop massive meningococcemia leading to shock and death is still not understood. © 2012 Springer Science+Business Media, LLC.

Ten Broek R.P.G.,Radboud University Nijmegen | Stommel M.W.J.,Radboud University Nijmegen | Strik C.,Radboud University Nijmegen | Van Laarhoven C.J.H.M.,Radboud University Nijmegen | And 2 more authors.
The Lancet | Year: 2014

Background Formation of adhesions after peritoneal surgery results in high morbidity. Barriers to prevent adhesion are seldom applied, despite their ability to reduce the severity of adhesion formation. We evaluated the benefits and harms of four adhesion barriers that have been approved for clinical use. Methods In this systematic review and meta-analysis, we searched PubMed, CENTRAL, and Embase for randomised clinical trials assessing use of oxidised regenerated cellulose, hyaluronate carboxy methylcellulose, icodextrin, or polyethylene glycol in abdominal surgery. Two researchers independently identified reports and extracted data. We compared use of a barrier with no barrier for nine predefined outcomes, graded for clinical relevance. The primary outcome was reoperation for adhesive small bowel obstruction. We assessed systematic error, random error, and design error with the error matrix approach. This study is registered with PROSPERO, number CRD42012003321. Findings Our search returned 1840 results, from which 28 trials (5191 patients) were included in our meta-analysis. The risks of systematic and random errors were low. No trials reported data for the effect of oxidised regenerated cellulose or polyethylene glycol on reoperations for adhesive small bowel obstruction. Oxidised regenerated cellulose reduced the incidence of adhesions (relative risk [RR] 0·51, 95% CI 0·31-0·86). Some evidence suggests that hyaluronate carboxymethylcellulose reduces the incidence of reoperations for adhesive small bowel obstruction (RR 0·49, 95% CI 0·28- 0·88). For icodextrin, reoperation for adhesive small bowel obstruction did not differ significantly between groups (RR 0·33, 95% CI 0·03-3·11). No barriers were associated with an increase in serious adverse events. Interpretation Oxidised regenerated cellulose and hyaluronate carboxymethylcellulose can safely reduce clinically relevant consequences of adhesions.

Gameiro S.,University of Coimbra | Gameiro S.,University of Cardiff | Boivin J.,University of Cardiff | Peronace L.,Merck Serono S.A. | Verhaak C.M.,Radboud University Nijmegen
Human Reproduction Update | Year: 2012

Background: Chances of achieving parenthood are high for couples who undergo fertility treatment. However, many choose to discontinue before conceiving. A systematic review was conducted to investigate patients' stated reasons for and predictors of discontinuation at five fertility treatment stages. Methods: Six databases were systematically searched. Search-terms referred to fertility treatment and discontinuation. Studies reporting on patients' stated reasons for or predictors of treatment discontinuation were included. A list of all reasons for discontinuation presented in each study was made, different categories of reasons were defined and the percentage of selections of each category was calculated. For each predictor, it was noted how many studies investigated it and how many found a positive and/or negative association with discontinuation. Results: The review included 22 studies that sampled 21 453 patients from eight countries. The most selected reasons for discontinuation were: postponement of treatment (39.18%, postponement of treatment or unknown 19.17%), physical and psychological burden (19.07%, psychological burden 14%, physical burden 6.32%), relational and personal problems (16.67%, personal reasons 9.27%, relational problems 8.83%), treatment rejection (13.23%) and organizational (11.68%) and clinic (7.71%) problems. Some reasons were common across stages (e.g. psychological burden). Others were stage-specific (e.g. treatment rejection during workup). None of the predictors reported were consistently associated with discontinuation. Conclusions: Much longitudinal and theory led research is required to explain discontinuation. Meanwhile, treatment burden should be addressed by better care organization and support for patients. Patients should be well informed, have the opportunity to discuss values and worries about treatment and receive advice to decide about continuing treatment. © The Author 2012. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.

Kuntsche E.,Radboud University Nijmegen
Drug and Alcohol Dependence | Year: 2012

Background: Memory deficits lead to distortion when long recall periods are used to assess alcohol consumption. We used the recently developed Internet-based cell phone-optimised assessment technique (ICAT) to describe the drinking patterns of young people over the course of Thursday, Friday and Saturday evenings and to compare the amounts reported during the drinking sessions in question with those in the retrospective baseline assessment. Methods: Using hyperlinks in text messages sent to their cell phones over five weeks, 183 young adults in French-speaking Switzerland completed a total of 8646 questionnaires at 8. pm, 9. pm, 10. pm, 11. pm, midnight and 11. am the next morning over 1441 evenings. Findings: Participants consumed an average of three drinks on Thursday evenings, four on Friday evenings and five and a half on Saturday evenings. The multi-group and multi-level latent growth curves showed that while the difference was minimal at the beginning of the evening, consumption decreased over the course of the evening on Thursdays, remained about stable on Fridays and increased on Saturdays between both genders. The amounts indicated in the evening assessments were up to twice as high as those indicated retrospectively. Conclusions: Using participants' cell phones, ICAT appears to be a convenient method for collecting alcohol-related data throughout the evening. Due to the significant impact of evening drinking patterns on the total amount consumed and related consequences, it is important to prevent the average increase of drinking that is likely to occur on Saturday evenings among young people. © 2012 Elsevier Ireland Ltd.

Kaliszyk C.,University of Innsbruck | Urban J.,Radboud University Nijmegen
Journal of Automated Reasoning | Year: 2014

The considerable mathematical knowledge encoded by the Flyspeck project is combined with external automated theorem provers (ATPs) and machine-learning premise selection methods trained on the Flyspeck proofs, producing an AI system capable of proving a wide range of mathematical conjectures automatically. The performance of this architecture is evaluated in a bootstrapping scenario emulating the development of Flyspeck from axioms to the last theorem, each time using only the previous theorems and proofs. It is shown that 39 % of the 14185 theorems could be proved in a push-button mode (without any high-level advice and user interaction) in 30 seconds of real time on a fourteen-CPU workstation. The necessary work involves: (i) an implementation of sound translations of the HOL Light logic to ATP formalisms: untyped first-order, polymorphic typed first-order, and typed higher-order, (ii) export of the dependency information from HOL Light and ATP proofs for the machine learners, and (iii) choice of suitable representations and methods for learning from previous proofs, and their integration as advisors with HOL Light. This work is described and discussed here, and an initial analysis of the body of proofs that were found fully automatically is provided. © 2014 The Author(s).

University of Groningen, Academisch Ziekenhuis Groningen and Radboud University Nijmegen | Date: 2011-03-23

An osseointegration system (1) for a long bone (2) comprises:- a sleeve system comprising at least two osseointegrated sleeves (4, 5) being mutually uncoupled in the sense that respective ones of the sleeves do not prevent one another to perform transverse displacements relative to one another;- a stem (6) arranged for being, in said operation condition, received within the at least two osseointegrated sleeves in such manner that at least low amplitude to-and-fro axial sliding displacements of the stem relative to said sleeves are allowed;- at least one fitting collar (7); and- retaining means (9) arranged for realizing that in said operation condition the stem is retained by the long bone.

Radboud University Nijmegen and Stichting Katholieke University | Date: 2012-01-11

The present invention relates to protein constructs that comprise one or more peptides, proteins, factors, compounds or other components as further described herein that are linked to and/or are linked to each other via a helical polymeric backbone. The constructs of the invention are suitable for administration to a human or animal body and can be used for pharmaceutical purposes, for example for immunotherapy such as for treating cancer and for other immunological applications, as well as for other therapeutic, prophylactic and/or diagnostic purposes.

News Article | November 13, 2015

The wave function of the collision between an NO molecule (red-white) and a helium atom (yellow) at the resonance energy. Credit: RU/Sjoerd Vogels For the first time, scientists have observed how molecules change direction after slow collisions with atoms. Researchers from Radboud University and the FOM Foundation allowed molecules to collide with atoms very slowly. This enabled them to zoom in on the dynamics of a collision for the first time. How do the initial conditions of particles transform into the final conditions after a collision? The results were published in the journal Science on 13 November 2015. According to the rules of quantum mechanics, a molecule often behaves as a series of waves. When a molecule collides with an atom, many different waves play roles in the interaction. These waves interfere during the collision and can give rise to a diffraction pattern. For years, scientists have tried to map the influence of a single wave in such a collision. It is fundamentally impossible to experimentally select a single wave and study its influence on a collision process. However, at very low temperatures, when molecules collide very slowly, this becomes possible under specific circumstances—during a so-called 'scattering resonance', a single wave suddenly dominates the collision process. In this case, it becomes possible to study precisely how a single wave before the collision determines the wave character of the particles after the collision. This is the essence of a collision at the most fundamental level: How do the starting conditions of particles transform into the final conditions after a collision? "We can now determine this by measuring the change in the molecules' flight direction during slow collisions," says FOM workgroup leader Bas van de Meerakker, whose awards include an ERC Starting Grant in 2013. "When the molecules collide slightly too quickly or too slowly, we observe a normal diffraction pattern of waves. However, if they have exactly the right velocity and hit a resonance, the change in direction is suddenly very different. A resonance can be conceived as a collision in which the particles briefly orbit around each other before separating and flying off in entirely different directions." The experimental measurements agree exactly with quantum mechanical calculations made by theoretical chemists Gerrit Groenenboom and Ad van der Avoird, co-authors of the article. With their theory, the researchers can now precisely determine which waves play a role during a scattering resonance and how these waves influence the molecules' change in flight direction. The Cold and Controlled Collisions laboratory at Radboud University has a Stark decelerator that the researchers can use to precisely control the velocity of the molecules before a collision. After a collision, they can accurately record the molecules' change in flight direction using the velocity map imaging method. This combination of techniques is only available at Radboud University. Thanks to this unique experiment, the researchers were able to observe these changes in the molecules' flight direction during a scattering resonance for the first time. Van de Meerakker received a Radboud Science Award in September 2015. This prize is awarded to the three best, most important and most fascinating scientific research results of Radboud University and Radboudumc during the past year. The awards ceremony is organised by the Science Hub Radboud University Nijmegen. The winners of the awards are given the opportunity to translate their research into activities for 10- to 12-year-old primary school pupils. With the help of experiments, Van de Meerakker will introduce the children to the fascinating world of quantum mechanics, including the wave character of matter. Explore further: Half-century-long quest to observe chemical reactions in quantum realm achieved More information: Publication: Imaging resonances in low-energy NO-He inelastic collisions, Sjoerd N. Vogels, Jolijn Onvlee, Simon Chefdeville, Ad van der Avoird, Gerrit C. Groenenboom, Sebastiaan Y.T. van de Meerakker, Science, 13 November 2015.

News Article | November 28, 2016

On November 11, the FSH Society honored four distinguished researchers and community members at their inaugural CureFSHD National Gala in Boston, Mass. The event, hosted by WBUR’s Morning Edition Host Bob Oakes, celebrated 25 years of progress towards finding a cure for Facioscapulohumeral Muscular Dystrophy (FSHD). The gala, which attracted more than 250 researchers, scientists, FSHD patients and supporters, was considered a great success by attendees and organizers alike. FSHD, one of the most prevalent types of muscular dystrophy, is a degenerative muscle disease that causes progressive weakness, usually starting with the face, shoulder, arms, legs and abdomen, but can spread to almost any skeletal muscle. FSHD affects approximately one million people yet, there is currently no treatment or cure. “Our inaugural National Gala was a chance for the entire FSHD community to come together to recognize exceptional individuals who have dedicated their lives and careers towards advancing FSHD related research,” said Daniel Perez, co-founder, President and CEO of the Lexington based non-profit FSH Society. “While there are many worthy candidates, this year we recognized a research pioneer whose work has played a major role in establishing the scientific foundations of the FSHD field and a young investigator who has published high-impact work and shows exceptional promise to develop into a leader. We also honored two pivotal members of the FSH Society community for their commitment to building the organization.” The 2016 FSH Society Pioneer Award was received by Dr. Ir. Silvère M. van der Maarel, who has made seminal contributions to the identification of the unifying genetic mechanism underlying FSHD. Professor van der Maarel was trained as a human geneticist at the Radboud University Nijmegen Medical Center in the Netherlands. His scientific interests focus on the genetic and epigenetic bases of FSHD. The 2016 FSH Society Young Investigator Award Winner was given to Charis L. Himeda, PhD, for many innovative studies, including her contributions to a ground-breaking 2015 paper published in Molecular Therapy. Dr. Himeda, an Instructor in Cell and Developmental Biology in the lab of Peter Jones at the University of Massachusetts Medical School, has published a widely noted study demonstrating the use of CRISPR gene-editing technology to suppress a gene that plays a key role in FSHD. The CureFSHD National Gala was also a chance for the FSH Society to recognize two extraordinary individuals who have provided many years of dedicated service to the FSH Society. Dr. David E. Housman, Ludwig Professor of Biology at Massachusetts Institute of Technology, is a renowned scientist and teacher who has been an inspiring mentor to hundreds of scientists for nearly half a century, raising awareness of FSHD by including it in the MD/PhD curriculum. Under his leadership as Chairman of the FSH Society’s Scientific Advisory Board, the SAB has reviewed hundreds of grant applications, resulting in $7 million in grants awarded to date and more than 300 publications in top-tier journals. Chris Stenmon, a dedicated member of the FSH Society served as a member of the FSH Society Board of Directors from 2006 to 2014, serving on the Finance and Development committees, as well as being treasurer for 2014. Mr. Stenmon was diagnosed with FSHD as a teenager and began his involvement with the Society by organizing and hosting a fundraiser beginning in 1998 which has since evolved into a major annual event raising nearly $300,000 over the years. “The FSH Society has been there for me whenever I needed them,” said Stenmon. The founders, “with their perseverance, drive, and will to never give up, are the main reasons we have made so much progress toward treatments and a cure.” About the FSH Society The FSH Society is a world leader in combating muscular dystrophy. The non-profit has provided millions of dollars in seed grants to pioneering research worldwide, creating an international collaborative network of patients and researchers. The FSH Society seeks to serve as a source of information and support for all patients and families with FSHD; act as a driving force in the development of research directed towards treatments and ultimately a cure; and bring support to patients and research for FSHD through effective engagement of governmental and private sector organizations and entities. For eight consecutive years, the Society has received the Charity Navigator’s four-star rating, the highest distinction held by less than two percent of non-profit organizations in the country. The FSH Society offers a community of support, news and information for FSHD patients and families through its website at For more information about FSHD, please contact the Society at 781-301-6649.

News Article | December 12, 2016

In 2015, the All Sky Automated Survey for SuperNovae (ASAS-SN) detected an event, named ASASSN-15lh, that was recorded as the brightest supernova ever -- and categorised as a superluminous supernova, the explosion of an extremely massive star at the end of its life. It was twice as bright as the previous record holder, and at its peak was 20 times brighter than the total light output of the entire Milky Way. An international team, led by Giorgos Leloudas at the Weizmann Institute of Science, Israel, and the Dark Cosmology Centre, Denmark, has now made additional observations of the distant galaxy, about 4 billion light-years from Earth, where the explosion took place and they have proposed a new explanation for this extraordinary event. "We observed the source for 10 months following the event and have concluded that the explanation is unlikely to lie with an extraordinarily bright supernova. Our results indicate that the event was probably caused by a rapidly spinning supermassive black hole as it destroyed a low-mass star," explains Leloudas. In this scenario, the extreme gravitational forces of a supermassive black hole, located in the centre of the host galaxy, ripped apart a Sun-like star that wandered too close -- a so-called tidal disruption event, something so far only observed about 10 times. In the process, the star was "spaghettified" and shocks in the colliding debris as well as heat generated in accretion led to a burst of light. This gave the event the appearance of a very bright supernova explosion, even though the star would not have become a supernova on its own as it did not have enough mass. The team based their new conclusions on observations from a selection of telescopes, both on the ground and in space. Among them was the Very Large Telescope at ESO's Paranal Observatory, the New Technology Telescope at ESO's La Silla Observatory and the NASA/ESA Hubble Space Telescope [1]. The observations with the NTT were made as part of the Public ESO Spectroscopic Survey of Transient Objects (PESSTO). "There are several independent aspects to the observations that suggest that this event was indeed a tidal disruption and not a superluminous supernova," explains coauthor Morgan Fraser from the University of Cambridge, UK (now at University College Dublin, Ireland). In particular, the data revealed that the event went through three distinct phases over the 10 months of follow-up observations. These data overall more closely resemble what is expected for a tidal disruption than a superluminous supernova. An observed re-brightening in ultraviolet light as well as a temperature increase further reduce the likelihood of a supernova event. Furthermore, the location of the event -- a red, massive and passive galaxy -- is not the usual home for a superluminous supernova explosion, which normally occur in blue, star-forming dwarf galaxies. Although the team say a supernova source is therefore very unlikely, they accept that a classical tidal disruption event would not be an adequate explanation for the event either. Team member Nicholas Stone from Columbia University, USA, elaborates: "The tidal disruption event we propose cannot be explained with a non-spinning supermassive black hole. We argue that ASASSN-15lh was a tidal disruption event arising from a very particular kind of black hole." The mass of the host galaxy implies that the supermassive black hole at its centre has a mass of at least 100 million times that of the Sun. A black hole of this mass would normally be unable to disrupt stars outside of its event horizon -- the boundary within which nothing is able to escape its gravitational pull. However, if the black hole is a particular kind that happens to be rapidly spinning -- a so-called Kerr black hole -- the situation changes and this limit no longer applies. "Even with all the collected data we cannot say with 100% certainty that the ASASSN-15lh event was a tidal disruption event," concludes Leloudas. "But it is by far the most likely explanation." [1] As well as the data from ESO's Very Large Telescope, the New Technology Telescope and the NASA/ESA Hubble Space Telescope the team used observations from NASA's Swift telescope, the Las Cumbres Observatory Global Telescope (LCOGT), the Australia Telescope Compact Array, ESA's XMM-Newton, the Wide-Field Spectrograph (WiFeS and the Magellan Telescope. This research was presented in a paper entitled "The Superluminous Transient ASASSN-15lh as a Tidal Disruption Event from a Kerr Black Hole", by G. Leloudas et al. to appear in the new Nature Astronomy magazine. The team is composed of G. Leloudas (Weizmann Institute of Science, Rehovot, Israel; Niels Bohr Institute, Copenhagen, Denmark), M. Fraser (University of Cambridge, Cambridge, UK), N. C. Stone (Columbia University, New York, USA), S. van Velzen (The Johns Hopkins University, Baltimore, USA), P. G. Jonker (Netherlands Institute for Space Research, Utrecht, the Netherlands; Radboud University Nijmegen, Nijmegen, the Netherlands), I. Arcavi (Las Cumbres Observatory Global Telescope Network, Goleta, USA; University of California, Santa Barbara, USA), C. Fremling (Stockholm University, Stockholm, Sweden), J. R. Maund (University of Sheffield, Sheffield, UK), S. J. Smartt (Queen's University Belfast, Belfast, UK), T. Krühler (Max-Planck-Institut für extraterrestrische Physik, Garching b. München, Germany), J. C. A. Miller-Jones (ICRAR - Curtin University, Perth, Australia), P. M. Vreeswijk (Weizmann Institute of Science, Rehovot, Israel), A. Gal-Yam (Weizmann Institute of Science, Rehovot, Israel), P. A. Mazzali (Liverpool John Moores University, Liverpool, UK; Max-Planck-Institut für Astrophysik, Garching b. München, Germany), A. De Cia (European Southern Observatory, Garching b. München, Germany), D. A. Howell (Las Cumbres Observatory Global Telescope Network, Goleta, USA; University of California Santa Barbara, Santa Barbara, USA), C. Inserra (Queen's University Belfast, Belfast, UK), F. Patat (European Southern Observatory, Garching b. München, Germany), A. de Ugarte Postigo (Instituto de Astrofisica de Andalucia, Granada, Spain; Niels Bohr Institute, Copenhagen, Denmark), O. Yaron (Weizmann Institute of Science, Rehovot, Israel), C. Ashall (Liverpool John Moores University, Liverpool, UK), I. Bar (Weizmann Institute of Science, Rehovot, Israel), H. Campbell (University of Cambridge, Cambridge, UK; University of Surrey, Guildford, UK), T.-W. Chen (Max-Planck-Institut für extraterrestrische Physik, Garching b. München, Germany), M. Childress (University of Southampton, Southampton, UK), N. Elias-Rosa (Osservatoria Astronomico di Padova, Padova, Italy), J. Harmanen (University of Turku, Piikkiö, Finland), G. Hosseinzadeh (Las Cumbres Observatory Global Telescope Network, Goleta, USA; University of California Santa Barbara, Santa Barbara, USA), J. Johansson (Weizmann Institute of Science, Rehovot, Israel), T. Kangas (University of Turku, Piikkiö, Finland), E. Kankare (Queen's University Belfast, Belfast, UK), S. Kim (Pontificia Universidad Católica de Chile, Santiago, Chile), H. Kuncarayakti (Millennium Institute of Astrophysics, Santiago, Chile; Universidad de Chile, Santiago, Chile), J. Lyman (University of Warwick, Coventry, UK), M. R. Magee (Queen's University Belfast, Belfast, UK), K. Maguire (Queen's University Belfast, Belfast, UK), D. Malesani (University of Copenhagen, Copenhagen, Denmark; DTU Space, Denmark), S. Mattila (University of Turku, Piikkiö, Finland; Finnish Centre for Astronomy with ESO (FINCA), University of Turku, Piikkiö, Finland; University of Cambridge, Cambridge, UK), C. V. McCully (Las Cumbres Observatory Global Telescope Network, Goleta, USA; University of California Santa Barbara, Santa Barbara, USA), M. Nicholl (Harvard-Smithsonian Center for Astrophysics, Cambridge, Massachusetts, USA), S. Prentice (Liverpool John Moores University, Liverpool, UK), C. Romero-Ca[ñ] - https:/ izales (Pontificia Universidad Católica de Chile, Santiago, Chile; Millennium Institute of Astrophysics, Santiago, Chile), S. Schulze (Pontificia Universidad Católica de Chile, Santiago, Chile; Millennium Institute of Astrophysics, Santiago, Chile), K. W. Smith (Queen's University Belfast, Belfast, UK), J. Sollerman (Stockholm University, Stockholm, Sweden), M. Sullivan (University of Southampton, Southampton, UK), B. E. Tucker (Australian National University, Canberra, Australia; ARC Centre of Excellence for All-sky Astrophysics (CAASTRO), Australia), S. Valenti (University of California, Davis, USA), J. C. Wheeler (University of Texas at Austin, Austin, USA), and D. R. Young (Queen's University Belfast, Belfast, UK). ESO is the foremost intergovernmental astronomy organisation in Europe and the world's most productive ground-based astronomical observatory by far. It is supported by 16 countries: Austria, Belgium, Brazil, the Czech Republic, Denmark, France, Finland, Germany, Italy, the Netherlands, Poland, Portugal, Spain, Sweden, Switzerland and the United Kingdom, along with the host state of Chile. ESO carries out an ambitious programme focused on the design, construction and operation of powerful ground-based observing facilities enabling astronomers to make important scientific discoveries. ESO also plays a leading role in promoting and organising cooperation in astronomical research. ESO operates three unique world-class observing sites in Chile: La Silla, Paranal and Chajnantor. At Paranal, ESO operates the Very Large Telescope, the world's most advanced visible-light astronomical observatory and two survey telescopes. VISTA works in the infrared and is the world's largest survey telescope and the VLT Survey Telescope is the largest telescope designed to exclusively survey the skies in visible light. ESO is a major partner in ALMA, the largest astronomical project in existence. And on Cerro Armazones, close to Paranal, ESO is building the 39-metre European Extremely Large Telescope, the E-ELT, which will become "the world's biggest eye on the sky".

News Article | November 14, 2015

Abstract: Physicists from the universities of Groningen and Nijmegen (the Netherlands) and Hong Kong have discovered that transistors made of ultrathin layers molybdeendisulfide (MoS2) are not only superconducting at low temperatures but also stay superconducting in a high magnetic field. This is a unique phenomenon with exciting promises for the future. The experiments were the first to have been performed at the High Field Magnet Laboratory in Nijmegen, jointly operated by Radboud University and the FOM foundation. The results are published on 12 November by the journal Science. Superconductivity is a state in which the electrical resistance of a material disappears completely. Normally, this phenomenon only exists at low temperatures and disappears under a high magnetic field. But in the High Field Magnet Laboratory (HFML), physicists discovered that MoS2 - which can be bought at the home depot stores as dry lubricant - remains superconducting under a high magnetic field of 37.5 Tesla. Strongly pinned electron pairs Superconductivity is induced when free electrons in a material are attracted to each other and form weakly bonded electron pairs. These pairs condensate to a superconducting state only when all possible disturbances in the material are minimal and therefore, superconductivity usually exists at very low temperature. When a material is exposed to a magnetic field, the weak bonding between the electron pair can be easily broken. The rupture of the pair destroys the superconductivity when disturbance from the magnetic field becomes strong enough. Surprisingly, the superconducting state of MoS2 survives high magnetic fields because the paired electrons are intrinsically associated with an internal high magnetic field, which can reach nearly one hundred Tesla, much higher than the 37.5 Tesla provided by the HFML. For comparison: a conventional fridge magnet has a magnetic field of approximately 0.1 Tesla. Uli Zeitler, physicist at the HFML at Radboud University explains: 'MoS2 behaves in a way that contradicts a law in physics, the so called Pauli paramagnetic limit.' Information in electron spin Although the current publication is very fundamental, Zeitler does have some ideas for future applications. 'There is information stored inside the charge and spin of electrons, the direction of their internal magnetic field. If you can influence this spin, for instance with an electric field, you can store information in there. And in principle, this technique could be used in the development of a future quantum computer.' The described experiments are complicated to perform. 'We execute this research at very low temperatures between 0 and 12 Kelvin, about minus 270 degrees Celsius, and under high magnetic fields. But in order to pump enough electrons into MoS2, we first needed relatively high temperatures of about minus 50 degrees Celsius', Zeitler explains. As the first external user of the newly-built 37.5 T magnet, Justin Ye, a physicist from Zernike Institute of Advanced Material at the University of Groningen is really excited by the result: 'It is a good starting point of this new facility. As the first user I am very happy to obtain this important result with the support from my colleagues in HFML. Following this breakthrough in identifying a new paring mechanism with stunning protection of superconductivity against high magnetic field, I would expect a lot of unexpected results from the future experiments in HFML.' ### Reference: Evidence for two-dimensional Ising superconductivity in gated MoS2 J. M. Lu, O. Zheliuk, I. Leermakers, Noah F. Q. Yuan, U. Zeitler, K. T. Law and J. T. Ye Science, 12 November 2015, DOI 10.1126/science.aab2277 The HFML is jointly operated by Radboud University Nijmegen and FOM, the Foundation for Fundamental Research on Matter. For more information, please click If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.

Rubartelli A.,Italian National Cancer Institute | Gattorno M.,G Gaslini Institute | Netea M.G.,Radboud University Nijmegen | Dinarello C.A.,Aurora University
Trends in Immunology | Year: 2011

Several inflammation-related processes, including inflammasome activation and interleukin (IL)-1β secretion, are dependent on redox signaling. However, the type of redox response involved as well as the relevant role of pro-oxidant and antioxidant events are matters of intense debate. By comparing leukemic myeloid cells, healthy monocytes and macrophages, as well as monocytes from patients carrying mutations in members of the Nod-like receptor (NLR) gene family, we have drawn a model that reconciles previous conflicting hypotheses. We propose that the redox state of resting inflammatory cells determines the type and extent of redox response to pattern recognition receptor stimulation, which in turn dictates the efficiency of inflammasome activation. The impact on genetic and acquired inflammatory diseases will be discussed. © 2011 Elsevier Ltd.

Hagoort P.,Max Planck Institute for Psycholinguistics | Hagoort P.,Radboud University Nijmegen | Indefrey P.,Radboud University Nijmegen | Indefrey P.,Heinrich Heine University Düsseldorf
Annual Review of Neuroscience | Year: 2014

A hallmark of human language is that we combine lexical building blocks retrieved from memory in endless new ways. This combinatorial aspect of language is referred to as unification. Here we focus on the neurobiological infrastructure for syntactic and semantic unification. Unification is characterized by a high-speed temporal profile including both prediction and integration of retrieved lexical elements. A meta-analysis of numerous neuroimaging studies reveals a clear dorsal/ventral gradient in both left inferior frontal cortex and left posterior temporal cortex, with dorsal foci for syntactic processing and ventral foci for semantic processing. In addition to core areas for unification, further networks need to be recruited to realize language-driven communication to its full extent. One example is the theory of mind network, which allows listeners and readers to infer the intended message (speaker meaning) from the coded meaning of the linguistic utterance. This indicates that sensorimotor simulation cannot handle all of language processing. © Copyright ©2014 by Annual Reviews. All rights reserved.

Fernandez I.,Complutense University of Madrid | Bickelhaupt F.M.,VU University Amsterdam | Bickelhaupt F.M.,Radboud University Nijmegen
Chemical Society Reviews | Year: 2014

In this Tutorial Review, we make the point that a true understanding of trends in reactivity (as opposed to measuring or simply computing them) requires a causal reactivity model. To this end, we present and discuss the Activation Strain Model (ASM). The ASM establishes the desired causal relationship between reaction barriers, on one hand, and the properties of reactants and characteristics of reaction mechanisms, on the other hand. In the ASM, the potential energy surface ΔE(ζ) along the reaction coordinate ζ is decomposed into the strain ΔEstrain(ζ) of the reactants that become increasingly deformed as the reaction proceeds, plus the interaction ΔEint(ζ) between these deformed reactants, i.e., ΔE(ζ) = ΔEstrain(ζ) + ΔE int(ζ). The ASM can be used in conjunction with any quantum chemical program. An analysis of the method and its application to problems in organic and organometallic chemistry illustrate the power of the ASM as a unifying concept and a tool for rational design of reactants and catalysts. This journal is © the Partner Organisations 2014.

Hogeveen M.,Radboud University Nijmegen | Blom H.J.,Metabolic | Den Heijer M.,Radboud University Nijmegen | Den Heijer M.,Medical Center
American Journal of Clinical Nutrition | Year: 2012

Background: Growth retardation in utero leading to small-for-gestational- age (SGA) newborns is associated with increased neonatal morbidity and mortality and with lifelong consequences such as poor cognitive function and cardiovascular diseases. Maternal total homocysteine (tHcy) concentrations have been linked to a wide range of adverse pregnancy outcomes and could possibly influence birth weight. Objective: We performed a systematic review of and meta-analysis on the association of maternal tHcy and birth weight. Design: A literature search of English, German, and French publications with the use of the PubMed database (January 1966-July 2010) found 78 abstracts. Search terms were as follows: homocysteine AND (birth weight OR small for gestational age OR intrauterine growth retardation). Studies were eligible if information on maternal tHcy and birth weight and the possible association between maternal tHcy and birth weight was available. Effect size estimates were converted to ORs as estimates of the RR of a woman to deliver SGA offspring when maternal tHcy exceeded the 90th percentile. Results: The search yielded 19 studies for analysis, consisting of 21,326 individuals. Pooled analysis resulted in a crude OR of 1.25 (95% CI: 1.09, 1.44). When this estimate was expressed as a linear effect, it corresponded to a decrease in birth weight of 31 g (95% CI: -13, -51 g) for a 1-SD increase in maternal tHcy. Conclusions: Higher maternal tHcy concentrations are associated with a small increased risk for SGA offspring. The small estimated birth weight difference might be of little clinical relevance for the individual newborn; however, it could be of greater importance at a population level. © 2012 American Society for Nutrition.

Karlebach G.,Max Planck Institute for Psycholinguistics | Francks C.,Max Planck Institute for Psycholinguistics | Francks C.,Radboud University Nijmegen
Cortex | Year: 2015

Lateralization is an important aspect of the functional brain architecture for language and other cognitive faculties. The molecular genetic basis of human brain lateralization is unknown, and recent studies have suggested that gene expression in the cerebral cortex is bilaterally symmetrical. Here we have re-analyzed two transcriptomic datasets derived from post mortem human cerebral cortex, with a specific focus on superior temporal and auditory language cortex in adults. We applied an empirical Bayes approach to model differential left-right expression, together with gene ontology (GO) analysis and meta-analysis. There was robust and reproducible lateralization of individual genes and GO groups that are likely to fine-tune the electrophysiological and neurotransmission properties of cortical circuits, most notably synaptic transmission, nervous system development and glutamate receptor activity. Our findings anchor the cerebral biology of language to the molecular genetic level. Future research in model systems may determine how these molecular signatures of neurophysiological lateralization effect fine-tuning of cerebral cortical function, differently in the two hemispheres. © 2015 Elsevier Ltd.

Lopez-Polin G.,Autonomous University of Madrid | Gomez-Navarro C.,Autonomous University of Madrid | Parente V.,CSIC - Institute of Materials Science | Guinea F.,CSIC - Institute of Materials Science | And 3 more authors.
Nature Physics | Year: 2015

The extraordinary strength, stiffness and lightness of graphene have generated great expectations of its application in flexible electronics and as a mechanical reinforcement agent. However, the presence of lattice defects, unavoidable in sheets obtained by scalable routes, might degrade its mechanical properties. Here we report a systematic study on the elastic modulus and strength of graphene with a controlled density of defects. Counter-intuitively, the in-plane Youngâ €™ s modulus increases with increasing defect density up to almost twice the initial value for a vacancy content of â 1/40.2%. For a higher density of vacancies, the elastic modulus decreases with defect inclusions. The initial increase in Youngâ €™ s modulus is explained in terms of a dependence of the elastic coefficients on the momentum of flexural modes predicted for two-dimensional membranes. In contrast, the fracture strength decreases with defect density according to standard fracture continuum models. These quantitative structure-property relationships, measured in atmospheric conditions, are of fundamental and technological relevance and provide guidance for applications in which graphene mechanics represents a disruptive improvement. © 2014 Macmillan Publishers Limited. All rights reserved.

Gershlick A.H.,University of Leicester | Banning A.P.,Oxford Radcliffe Hospitals | Myat A.,King's College London | Verheugt F.W.A.,Radboud University Nijmegen | Gersh B.J.,Mayo Medical School
The Lancet | Year: 2013

In the past ten years, primary percutaneous coronary intervention (PCI) has replaced thrombolysis as the revascularisation strategy for many patients presenting with ST-segment elevation myocardial infarction (STEMI). However, delivery of primary PCI within evidence-based timeframes is challenging, and health-care provision varies substantially worldwide. Consequently, even with the ideal circumstances of rapid initial diagnosis, long transfer delays to the catheter laboratory can occur. These delays are detrimental to outcomes for patients and can be exaggerated by variations in timing of patients' presentation and diagnosis. In this Series paper we summarise the value of immediate out-of-hospital thrombolysis for STEMI, and reconsider the potential therapeutic interface with a contemporary service for primary PCI. We review recent trial data, and explore opportunities for optimisation of STEMI outcomes with a pharmacoinvasive approach.

Wesseling P.,VU University Amsterdam | Wesseling P.,Radboud University Nijmegen | van den Bent M.,Erasmus Cancer Center | Perry A.,University of California at San Francisco
Acta Neuropathologica | Year: 2015

For nearly a century, the diagnosis and grading of oligodendrogliomas and oligoastrocytomas has been based on histopathology alone. Roughly 20 years ago, the first glioma-associated molecular signature was found with complete chromosome 1p and 19q codeletion being particularly common in histologically classic oligodendrogliomas. Subsequently, this codeletion appeared to not only carry diagnostic, but also prognostic and predictive information, the latter aspect only recently resolved after carefully constructed clinical trials with very long follow-up times. More recently described biomarkers, including the non-balanced translocation leading to 1p/19q codeletion, promoter hypermethylation of the MGMT gene, mutations of the IDH1 or IDH2 gene, and mutations of FUBP1 (on 1p) or CIC (on 19q), have greatly enhanced our understanding of oligodendroglioma biology, although their diagnostic, prognostic, and predictive roles are less clear. It has therefore been suggested that complete 1p/19q codeletion be required for the diagnosis of ‘canonical oligodendroglioma’. This transition to an integrated morphological and molecular diagnosis may result in the disappearance of oligoastrocytoma as an entity, but brings new challenges as well. For instance it needs to be sorted out how (histopathological) criteria for grading of ‘canonical oligodendrogliomas’ should be adapted, how pediatric oligodendrogliomas (known to lack codeletions) should be defined, which platforms and cut-off levels should ideally be used for demonstration of particular molecular aberrations, and how the diagnosis of oligodendroglioma should be made in centers/countries where molecular diagnostics is not available. Meanwhile, smart integration of morphological and molecular information will lead to recognition of biologically much more uniform groups within the spectrum of diffuse gliomas and thereby facilitate tailored treatments for individual patients. © 2015, The Author(s).

Schuler M.,University of Bremen | Rosner M.,University of Bremen | Wehling T.O.,University of Bremen | Lichtenstein A.I.,University of Hamburg | Katsnelson M.I.,Radboud University Nijmegen
Physical Review Letters | Year: 2013

To understand how nonlocal Coulomb interactions affect the phase diagram of correlated electron materials, we report on a method to approximate a correlated lattice model with nonlocal interactions by an effective Hubbard model with on-site interactions U* only. The effective model is defined by the Peierls-Feynman-Bogoliubov variational principle. We find that the local part of the interaction U is reduced according to U *=U-V̄, where V̄ is a weighted average of nonlocal interactions. For graphene, silicene, and benzene we show that the nonlocal Coulomb interaction can decrease the effective local interaction by more than a factor of 2 in a wide doping range. © 2013 American Physical Society.

Watt F.M.,King's College London | Huck W.T.S.,Radboud University Nijmegen
Nature Reviews Molecular Cell Biology | Year: 2013

The field of stem cells and regenerative medicine offers considerable promise as a means of delivering new treatments for a wide range of diseases. In order to maximize the effectiveness of cell-based therapies-whether stimulating expansion of endogenous cells or transplanting cells into patients-it is essential to understand the environmental (niche) signals that regulate stem cell behaviour. One of those signals is from the extracellular matrix (ECM). New technologies have offered insights into how stem cells sense signals from the ECM and how they respond to these signals at the molecular level, which ultimately regulate their fate. © 2013 Macmillan Publishers Limited. All rights reserved.

van der Zee A.,Maasstad Hospital | Schellekens J.F.P.,Certe Laboratory for Infectious Diseases | Mooi F.R.,National Institute for Public Health and the Environment | Mooi F.R.,Radboud University Nijmegen
Clinical Microbiology Reviews | Year: 2015

The introduction of vaccination in the 1950s significantly reduced the morbidity and mortality of pertussis. However, since the 1990s, a resurgence of pertussis has been observed in vaccinated populations, and a number of causes have been proposed for this phenomenon, including improved diagnostics, increased awareness, waning immunity, and pathogen adaptation. The resurgence of pertussis highlights the importance of standardized, sensitive, and specific laboratory diagnoses, the lack of which is responsible for the large differences in pertussis notifications between countries. Accurate laboratory diagnosis is also important for distinguishing between the several etiologic agents of pertussis-like diseases, which involve both viruses and bacteria. If pertussis is diagnosed in a timely manner, antibiotic treatment of the patient can mitigate the symptoms and prevent transmission. During an outbreak, timely diagnosis of pertussis allows prophylactic treatment of infants too young to be (fully) vaccinated, for whom pertussis is a severe, sometimes fatal disease. Finally, reliable diagnosis of pertussis is required to reveal trends in the (age-specific) disease incidence, which may point to changes in vaccine efficacy, waning immunity, and the emergence of vaccine-adapted strains. Here we review current approaches to the diagnosis of pertussis and discuss their limitations and strengths. In particular, we emphasize that the optimal diagnostic procedure depends on the stage of the disease, the age of the patient, and the vaccination status of the patient. © 2015, American Society for Microbiology. All Rights Reserved.

Mani N.,University of Gottingen | Huettig F.,Max Planck Institute for Psycholinguistics | Huettig F.,Radboud University Nijmegen
Journal of Experimental Child Psychology | Year: 2014

Despite the efficiency with which language users typically process spoken language, a growing body of research finds substantial individual differences in both the speed and accuracy of spoken language processing potentially attributable to participants' literacy skills. Against this background, the current study took a look at the role of word reading skill in listeners' anticipation of upcoming spoken language input in children at the cusp of learning to read; if reading skills affect predictive language processing, then children at this stage of literacy acquisition should be most susceptible to the effects of reading skills on spoken language processing. We tested 8-year-olds on their prediction of upcoming spoken language input in an eye-tracking task. Although children, like in previous studies to date, were successfully able to anticipate upcoming spoken language input, there was a strong positive correlation between children's word reading skills (but not their pseudo-word reading and meta-phonological awareness or their spoken word recognition skills) and their prediction skills. We suggest that these findings are most compatible with the notion that the process of learning orthographic representations during reading acquisition sharpens pre-existing lexical representations, which in turn also supports anticipation of upcoming spoken words. © 2014 Elsevier Inc.

Ozyurek A.,Radboud University Nijmegen | Ozyurek A.,Max Planck Institute for Psycholinguistics
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

As we speak, we use not only the arbitrary form-meaning mappings of the speech channel but also motivated form-meaning correspondences, i.e. iconic gestures that accompany speech (e.g. inverted V-shaped hand wiggling across gesture space to demonstrate walking). This article reviews what we know about processing of semantic information from speech and iconic gestures in spoken languages during comprehension of such composite utterances. Several studies have shown that comprehension of iconic gestures involves brain activations known to be involved in semantic processing of speech: i.e. modulation of the electrophysiological recording component N400, which is sensitive to the ease of semantic integration of a word to previous context, and recruitment of the left-lateralized frontal-posterior temporal network (left inferior frontal gyrus (IFG), medial temporal gyrus (MTG) and superior temporal gyrus/sulcus (STG/S)). Furthermore, we integrate the information coming from both channels recruiting brain areas such as left IFG, posterior superior temporal sulcus (STS)/MTG and even motor cortex. Finally, this integration is flexible: the temporal synchrony between the iconic gesture and the speech segment, as well as the perceived communicative intent of the speaker, modulate the integration process. Whether these findings are special to gestures or are shared with actions or other visual accompaniments to speech (e.g. lips) or other visual symbols such as pictures are discussed, as well as the implications for a multimodal view of language. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Parwati I.,Padjadjaran University | van Crevel R.,Radboud University Nijmegen | van Soolingen D.,National Institute for Public Health and the Environment
The Lancet Infectious Diseases | Year: 2010

The wide geographic distribution of one clade of Mycobacterium tuberculosis, the Beijing genotype family, and its genetic homogeneity, suggests that strains belonging to this grouping might have a selective advantage over other M tuberculosis strains. This hypothesis was addressed by reviewing molecular-epidemiological, experimental, and clinical studies. Beijing strains represent about 50% of strains in east Asia and at least 13% of strains worldwide. Their emergence might be linked to escape from BCG vaccination, and to multidrug resistance, which is associated with the Beijing genotype in many areas. Different animal models have shown Beijing strains to be more virulent, and to cause more histopathological changes, higher outgrowth, and increased mortality. At a molecular level, Beijing strains have specific properties in terms of protein and lipid structures and their interaction with the human immune system. Finally, the Beijing genotype has been linked to polymorphisms in immune genes, suggesting the possibility of human-mycobacterial co-evolution. The emergence of the Beijing genotype family might represent an evolutionary response of M tuberculosis to vaccination or antibiotic treatment, with an important negative impact on tuberculosis control. More research is needed to further unravel the mechanisms underlying the emergence of M tuberculosis Beijing genotype strains, and examine the implications for future control strategies. © 2010 Elsevier Ltd. All rights reserved.

Ruslami R.,Padjadjaran University | Ganiem A.R.,Padjadjaran University | Dian S.,Padjadjaran University | Apriani L.,Padjadjaran University | And 5 more authors.
The Lancet Infectious Diseases | Year: 2013

Background: Intensified antibiotic treatment might improve the outcome of tuberculous meningitis. We assessed pharmacokinetics, safety, and survival benefit of several treatment regimens containing high-dose rifampicin and moxifloxacin in patients with tuberculous meningitis in a hospital setting. Methods: In an open-label, phase 2 trial with a factorial design in one hospital in Indonesia, patients (aged >14 years) with tuberculous meningitis were randomly assigned to receive, according to a computer-generated schedule, first rifampicin standard dose (450 mg, about 10 mg/kg) orally or high dose (600 mg, about 13 mg/kg) intravenously, and second oral moxifloxacin 400 mg, moxifloxacin 800 mg, or ethambutol 750 mg once daily. All patients were given standard-dose isoniazid, pyrazinamide, and adjunctive corticosteroids. After 14 days of treatment all patients continued with standard treatment for tuberculosis. Endpoints included pharmacokinetic analyses of the blood and cerebrospinal fluid, adverse events attributable to tuberculosis treatment, and survival. Analysis was by intention to treat. This trial is registered with, number NCT01158755. Findings: 60 patients were randomly assigned to receive rifampicin standard dose (12 no moxifloxacin, ten moxifloxacin 400 mg, and nine moxifloxacin 800 mg) and high dose (ten no moxifloxacin, nine moxifloxacin 400 mg, and ten moxifloxacin 800 mg). A 33% higher dose of rifampicin, intravenously, led to a three times higher geometric mean area under the time-concentration curve up to 6 h after dose (AUC0-6; 78·7 mg.h/L [95% CI 71·0-87·3] vs 26·0 mg.h/L [19·0-35·6]), maximum plasma concentrations (Cmax; 22·1 mg/L [19·9-24·6] vs 6·3 mg/L [4·9-8·3]), and concentrations in cerebrospinal fluid (0·60 mg/L [0·46-0·78] vs 0·21 mg/L [0·16-0·27]). Doubling the dose of moxifloxacin resulted in a proportional increase in plasma AUC0-6 (31·5 mg.h/L [24·1-41·1] vs 15·1 mg.h/L [12·8-17·7]), Cmax (7·4 mg/L [5·6-9·6] vs 3·9 mg/L [3·2-4·8]), and drug concentrations in the cerebrospinal fluid (2·43 mg/L [1·81-3·27] vs 1·52 mg/L [1·28-1·82]). Intensified treatment did not result in increased toxicity. 6 month mortality was substantially lower in patients given high-dose rifampicin intravenously (ten [35%] vs 20 [65%]), which could not be explained by HIV status or severity of disease at the time of presentation (adjusted HR 0·42; 95% CI 0·20-0·91; p=0·03). Interpretation: These data suggest that treatment containing a higher dose of rifampicin and standard-dose or high-dose moxifloxacin during the first 2 weeks is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease. Funding: Royal Dutch Academy of Arts and Sciences, Netherlands Foundation for Scientific Research, and Padjadjaran University, Bandung, Indonesia. © 2013 Elsevier Ltd.

Van De Meerakker S.Y.T.,Radboud University Nijmegen | Bethlem H.L.,VU University Amsterdam | Vanhaecke N.,University Paris - Sud | Meijer G.,Fritz Haber Institute
Chemical Reviews | Year: 2012

A study was conducted to demonstrate the manipulation of molecular beams with electric and magnetic fields. Seeded pulsed supersonic expansions were employed to conduct the investigations. The conservative forces exerted further downstream by the electric and magnetic fields enabled the researchers to manipulate and control the shape and the position of the distribution in the six-dimensional phase-space. All of the original experimental geometries were devised to create strong magnetic or electric field gradients to efficiently deflect particles from the beam axis. It was demonstrated that a detailed understanding of the influence of the external field on the energy level structure of the molecules was required for the manipulation of molecules with electric or magnetic fields.

Wehling T.O.,University of Hamburg | SasIoglu E.,Jülich Research Center | Friedrich C.,Jülich Research Center | Lichtenstein A.I.,University of Hamburg | And 2 more authors.
Physical Review Letters | Year: 2011

To obtain an effective many-body model of graphene and related materials from first principles we calculate the partially screened frequency dependent Coulomb interaction. In graphene, the effective on-site (Hubbard) interaction is U00=9.3eV in close vicinity to the critical value separating conducting graphene from an insulating phase emphasizing the importance of nonlocal Coulomb terms. The nearest-neighbor Coulomb interaction strength is computed to U01=5.5eV. In the long-wavelength limit, we find the effective background dielectric constant of graphite to be ε=2.5 in very good agreement with experiment. © 2011 American Physical Society.

Basnakova J.,Max Planck Institute for Psycholinguistics | Weber K.,Radboud University Nijmegen | Petersson K.M.,Max Planck Institute for Psycholinguistics | van Berkum J.,Max Planck Institute for Psycholinguistics | Hagoort P.,Max Planck Institute for Psycholinguistics
Cerebral cortex (New York, N.Y. : 1991) | Year: 2014

Even though language allows us to say exactly what we mean, we often use language to say things indirectly, in a way that depends on the specific communicative context. For example, we can use an apparently straightforward sentence like "It is hard to give a good presentation" to convey deeper meanings, like "Your talk was a mess!" One of the big puzzles in language science is how listeners work out what speakers really mean, which is a skill absolutely central to communication. However, most neuroimaging studies of language comprehension have focused on the arguably much simpler, context-independent process of understanding direct utterances. To examine the neural systems involved in getting at contextually constrained indirect meaning, we used functional magnetic resonance imaging as people listened to indirect replies in spoken dialog. Relative to direct control utterances, indirect replies engaged dorsomedial prefrontal cortex, right temporo-parietal junction and insula, as well as bilateral inferior frontal gyrus and right medial temporal gyrus. This suggests that listeners take the speaker's perspective on both cognitive (theory of mind) and affective (empathy-like) levels. In line with classic pragmatic theories, our results also indicate that currently popular "simulationist" accounts of language comprehension fail to explain how listeners understand the speaker's intended message. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:

Hessels D.,NovioGendix BV | Schalken J.A.,Radboud University Nijmegen
Asian Journal of Andrology | Year: 2013

Although the routine use of serum prostate-specific antigen (PSA) testing has undoubtedly increased prostate cancer (PCa) detection, one of its main drawbacks is its lack of specificity. As a consequence, many men undergo unnecessary biopsies or treatments for indolent tumours. PCa-specific markers are needed for the early detection of the disease and the prediction of aggressiveness of a prostate tumour. Since PCa is a heterogeneous disease, a panel of tumour markers is fundamental for a more precise diagnosis. Several biomarkers are promising due to their specificity for the disease in tissue. However, tissue is unsuitable as a possible screening tool. Since urine can be easily obtained in a non-invasive manner, it is a promising substrate for biomarker testing. This article reviews the biomarkers for the non-invasive testing of PCa in urine. © 2013 AJA, SIMM & SJTU. All rights reserved.

Luttjohann A.,Radboud University Nijmegen | Schoffelen J.-M.,Radboud University Nijmegen | Schoffelen J.-M.,Max Planck Institute for Psycholinguistics | van Luijtelaar G.,Radboud University Nijmegen
Neurobiology of Disease | Year: 2014

Purpose: While decades of research were devoted to study generation mechanisms of spontaneous spike and wave discharges (SWD), little attention has been paid to network mechanisms associated with the spontaneous termination of SWD. In the current study coupling-dynamics at the onset and termination of SWD were studied in an extended part of the cortico-thalamo-cortical system of freely moving, genetic absence epileptic WAG/Rij rats. Methods: Local-field potential recordings of 16 male WAG/Rij rats, equipped with multiple electrodes targeting layer 4 to 6 of the somatosensory-cortex (ctx4, ctx5, ctx6), rostral and caudal reticular thalamic nucleus (rRTN & cRTN), ventral postero medial (VPM), anterior- (ATN) and posterior (Po) thalamic nucleus, were obtained. Six seconds lasting pre-SWD- > SWD, SWD- > post SWD and control periods were analyzed with time-frequency methods, and between-region interactions were quantified with frequency-resolved Granger Causality (GC) analysis. Results: Most channel pairs showed increases in GC lasting from onset to offset of the SWD. While for most thalamo-thalamic pairs a dominant coupling direction was found during the complete SWD, most cortico-thalamic pairs only showed a dominant directional drive (always from cortex to thalamus) during the first 500. ms of SWD. Channel pair ctx4-rRTN showed a longer lasting dominant cortical drive, which stopped 1.5. sec prior to SWD offset. This early decrease in directional coupling was followed by an increase in directional coupling from cRTN to rRTN 1. sec prior to SWD offset. For channel pairs ctx5-Po and ctx6-Po the heightened cortex- > thalamus coupling remained until 1.5 sec following SWD offset, while the thalamus- > cortex coupling for these pairs stopped at SWD offset. Conclusion: The high directional coupling from somatosensory cortex to the thalamus at SWD onset is in good agreement with the idea of a cortical epileptic focus that initiates and entrains other brain structures into seizure activity. The decrease of cortex to rRTN coupling as well as the increased coupling from cRTN to rRTN preceding SWD termination demonstrates that SWD termination is a gradual process that involves both cortico-thalamic as well as intrathalamic processes. The rostral RTN seems to be an important resonator for SWD and relevant for maintenance, while the cRTN might inhibit this oscillation. The somatosensory cortex seems to attempt to reinitiate SWD following its offset via its strong coupling to the posterior thalamus. © 2014 Elsevier Inc.

Levinson S.C.,Max Planck Institute for Psycholinguistics | Levinson S.C.,Radboud University Nijmegen | Holler J.,Max Planck Institute for Psycholinguistics
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

One reason for the apparent gulf between animal and human communication systems is that the focus has been on the presence or the absence of language as a complex expressive system built on speech. But language normally occurs embedded within an interactional exchange of multi-modal signals. If this larger perspective takes central focus, then it becomes apparent that human communication has a layered structure, where the layers may be plausibly assigned different phylogenetic and evolutionary origins-especially in the light of recent thoughts on the emergence of voluntary breathing and spoken language. This perspective helps us to appreciate the different roles that the different modalities play in human communication, as well as how they function as one integrated system despite their different roles and origins. It also offers possibilities for reconciling the 'gesture-first hypothesis' with that of gesture and speech having evolved together, hand in hand-or hand in mouth, rather-as one system. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Lionakis M.S.,National Institute of Allergy and Infectious Diseases | Netea M.G.,Radboud University Nijmegen | Holland S.M.,National Institute of Allergy and Infectious Diseases
Cold Spring Harbor Perspectives in Medicine | Year: 2014

A recent surge in newly described inborn errors of immune function-related genes that result in susceptibility to fungal disease has greatly enhanced our understanding of the cellular and molecular basis of antifungal immune responses. Characterization of single-gene defects that predispose to various combinations of superficial and deep-seated infections caused by yeasts, molds, and dimorphic fungi has unmasked the critical role of novel molecules and signaling pathways in mucosal and systemic antifungal host defense. These experiments of nature offer a unique opportunity for developing new knowledge in immunological research and form the foundation for devising immune-based therapeutic approaches for patients infected with fungal pathogens. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

Mani N.,University of Gottingen | Huettig F.,Max Planck Institute for Psycholinguistics | Huettig F.,Radboud University Nijmegen
Journal of Experimental Psychology: Human Perception and Performance | Year: 2012

Are there individual differences in children's prediction of upcoming linguistic input and what do these differences reflect? Using a variant of the preferential looking paradigm (Golinkoff, Hirsh-Pasek, Cauley, & Gordon, 1987), we found that, upon hearing a sentence like, "The boy eats a big cake," 2-year-olds fixate edible objects in a visual scene (a cake) soon after they hear the semantically constraining verb eats and prior to hearing the word cake. Importantly, children's prediction skills were significantly correlated with their productive vocabulary size-skilled producers (i.e., children with large production vocabularies) showed evidence of predicting upcoming linguistic input, while low producers did not. Furthermore, we found that children's prediction ability is tied specifically to their production skills and not to their comprehension skills. Prediction is really a piece of cake, but only for skilled producers. © 2012 American Psychological Association.

Nettle D.,Northumbria University | Frankenhuis W.E.,Radboud University Nijmegen | Rickard I.J.,Durham University
Proceedings of the Royal Society B: Biological Sciences | Year: 2013

Many studies in humans have shown that adverse experience in early life is associated with accelerated reproductive timing, and there is comparative evidence for similar effects in other animals. There are two different classes of adaptive explanation for associations between early-life adversity and accelerated reproduction, both based on the idea of predictive adaptive responses (PARs). According to external PAR hypotheses, early-life adversity provides a 'weather forecast' of the environmental conditions into which the individual will mature, and it is adaptive for the individual to develop an appropriate phenotype for this anticipated environment. In internal PAR hypotheses, early-life adversity has a lasting negative impact on the individual's somatic state, such that her health is likely to fail more rapidly as she gets older, and there is an advantage to adjusting her reproductive schedule accordingly. We use a model of fluctuating environments to derive evolveability conditions for acceleration of reproductive timing in response to early-life adversity in a long-lived organism. For acceleration to evolve via the external PAR process, early-life cues must have a high degree of validity and the level of annual autocorrelation in the individual's environment must be almost perfect. For acceleration to evolve via the internal PAR process requires that early-life experience must determine a significant fraction of the variance in survival prospects in adulthood. The two processes are not mutually exclusive, and mechanisms for calibrating reproductive timing on the basis of early experience could evolve through a combination of the predictive value of early-life adversity for the later environment and its negative impact on somatic state. © 2013 The Author(s) Published by the Royal Society. All rights reserved.

Fernandez I.,Complutense University of Madrid | Sola M.,University of Girona | Bickelhaupt F.M.,VU University Amsterdam | Bickelhaupt F.M.,Radboud University Nijmegen
Chemistry - A European Journal | Year: 2013

The origin of the experimentally known preference for [6,6] over [5,6] bonds in cycloaddition reactions involving C60 has been computationally explored. To this end, the Diels-Alder reaction between cyclopentadiene and C60 has been analysed by means of the recently introduced activation strain model of reactivity in combination with the energy decomposition analysis method. Other issues, such as the aromaticity of the corresponding transition states, have also been considered. These results indicate that the major factor controlling the observed regioselectivity is the more stabilising interaction between the deformed reactants in the [6,6] reaction pathway along the entire reaction coordinate. Why [6,6]? The preference for [6,6] over [5,6] bonds in cycloaddition reactions involving C60 is experimentally well-established (see figure). However, the reasons (i.e., physical factors) behind this preference are so far completely unknown. By means of the recently introduced activation strain model of reactivity in combination with the energy decomposition analysis method, a definite answer to the question in the title is provided. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Kelly S.D.,Colgate University | Ozyurek A.,Radboud University Nijmegen | Ozyurek A.,Max Planck Institute for Psycholinguistics | Maris E.,Radboud University Nijmegen
Psychological Science | Year: 2010

Gesture and speech are assumed to form an integrated system during language production. Based on this view, we propose the integrated-systems hypothesis, which explains two ways in which gesture and speech are integrated-through mutual and obligatory interactions-in language comprehension. Experiment 1 presented participants with action primes (e.g., someone chopping vegetables) and bimodal speech and gesture targets. Participants related primes to targets more quickly and accurately when they contained congruent information (speech: "chop"; gesture: chop) than when they contained incongruent information (speech: "chop"; gesture: twist). Moreover, the strength of the incongruence affected processing, with fewer errors for weak incongruities (speech: "chop"; gesture: cut) than for strong incongruities (speech: "chop"; gesture: twist). Crucial for the integrated-systems hypothesis, this influence was bidirectional. Experiment 2 demonstrated that gesture's influence on speech was obligatory. The results confirm the integrated-systems hypothesis and demonstrate that gesture and speech form an integrated system in language comprehension. © The Author(s) 2010.

Hessels D.,NovioGendix BV | Schalken J.A.,Radboud University Nijmegen
Current Urology Reports | Year: 2013

Gene fusions, resulting from chromosomal rearrangements, have been attributed to leukaemias and soft tissue sarcomas. The recent discovery of a recurrent gene fusion TMPRSS2-ERG in approximately half of the prostate cancers tested indicates that gene fusions also play a role in the onset of common epithelial cancers. Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in the Western male population. It is a heterogeneous disease, both in terms of pathology and clinical presentation. Since the discovery of the TMPRSS2-ERG fusion, other gene fusions have been reported, most of which result in the androgen-regulated over-expression of the oncogene ERG or other ETS transcription factors. The high prevalence of these gene fusions represents a distinct class of tumours, which may give more insight in the heterogeneity of the disease. These gene fusions are of interest as biomarkers for diagnosis of prostate cancer, and some of them could be useful in predicting the presence of aggressive disease. This review focuses on the biological significance and clinical implementation of gene fusions, and particularly the most commonly reported TMPRSS2-ERG fusion, in prostate cancer. © 2013 Springer Science+Business Media New York.

Cools R.,Radboud University Nijmegen | Nakamura K.,Kansai Medical University | Daw N.D.,New York University
Neuropsychopharmacology | Year: 2011

Serotonin, like dopamine (DA), has long been implicated in adaptive behavior, including decision making and reinforcement learning. However, although the two neuromodulators are tightly related and have a similar degree of functional importance, compared with DA, we have a much less specific understanding about the mechanisms by which serotonin affects behavior. Here, we draw on recent work on computational models of dopaminergic function to suggest a framework by which many of the seemingly diverse functions associated with both DA and serotoninFcomprising both affective and activational ones, as well as a number of other functions not overtly related to eitherFcan be seen as consequences of a single root mechanism. © 2011 Nature Publishing Group All rights reserved.

Yuan S.,Radboud University Nijmegen | Wehling T.O.,University of Bremen | Lichtenstein A.I.,University of Hamburg | Katsnelson M.I.,Radboud University Nijmegen
Physical Review Letters | Year: 2012

Resonant scatterers such as hydrogen adatoms can strongly enhance the low-energy density of states in graphene. Here, we study the impact of these impurities on electronic screening. We find a two-faced behavior: Kubo formula calculations reveal an increased dielectric function ε upon creation of midgap states but no metallic divergence of the static ε at small momentum transfer q→0. This bad metal behavior manifests also in the dynamic polarization function and can be directly measured by means of electron energy loss spectroscopy. A new length scale l c beyond which screening is suppressed emerges, which we identify with the Anderson localization length. © 2012 American Physical Society.

McQueen J.M.,Radboud University Nijmegen | Huettig F.,Max Planck Institute for Psycholinguistics
Journal of the Acoustical Society of America | Year: 2012

An eye-tracking experiment examined contextual flexibility in speech processing in response to distortions in spoken input. Dutch participants heard Dutch sentences containing critical words and saw four-picture displays. The name of one picture either had the same onset phonemes as the critical word or had a different first phoneme and rhymed. Participants fixated on onset-overlap more than rhyme-overlap pictures, but this tendency varied with speech quality. Relative to a baseline with noise-free sentences, participants looked less at onset-overlap and more at rhyme-overlap pictures when phonemes in the sentences (but not in the critical words) were replaced by noises like those heard on a badly tuned AM radio. The position of the noises (word-initial or word-medial) had no effect. Noises elsewhere in the sentences apparently made evidence about the critical word less reliable: Listeners became less confident of having heard the onset-overlap name but also less sure of having not heard the rhyme-overlap name. The same acoustic information has different effects on spoken-word recognition as the probability of distortion changes. © 2012 Acoustical Society of America.

News Article | October 27, 2015

Figure 1. In A, the droplets are situated in a non-viscous environement and in B they have a higher viscosity. Bacteria are incredibly small, yet pack an enormous diversity of different molecules such as DNA, mRNA and proteins. Chemists from Radboud University Nijmegen, Eindhoven and Paris now show for the first time that random variations or 'noise' in cellular processes come to exist because of an interplay between the rate of the reaction and its environment. Nature Nanotechnology publishes the results on October 26. In a living cell, many processes are continuously going on at the same time. Because of that, many different components are present in minute quantities, which inevitably leads to random variations in cellular processes which are also called 'noise' by chemists. Until now, the exact origin of the noise had never been fully explained. Maike Hansen, chemist at Radboud University and first author of the article, explains: 'To investigate the noise phenomenon, we placed DNA molecules in hundreds of tiny picolitre fluid droplets.' All the droplets had the exact same composition, allowing the researchers to investigate them at the same time and look at the noise that originated from the small variations between them. 'We discovered that as the viscosity or the stickiness of the droplets increases, the noise in the cells also increases', Hansen says. 'More into detail, we found out that in viscous environments, of which living cells are an example, the mobility of produced macromolecules like proteins declines. Because of that, the macromolecules are produced faster than they can diffuse away, leading to local reaction hotspots. These hotspots lead to a significant increase in noise, something we confirmed using simulations.' When asked about the importance of this finding, Hansen explains: 'We want to understand why cells are different from each other. For instance, why can different bacteria with the same basic information in their DNA be resistant or non-resistant to antibiotics? Those differences can be explained by the small variations that we measured. Furthermore, it is our aim to build a synthetic cell in the lab one day. To achieve this, we have to know all the details about cells and their reactions. So finding out that viscosity is important, is very important to us.' Explore further: Paper describes new method to understand sources of noise in gene-expression More information: Maike M. K. Hansen et al. Macromolecular crowding creates heterogeneous environments of gene expression in picolitre droplets, Nature Nanotechnology (2015). DOI: 10.1038/nnano.2015.243

News Article | December 15, 2015

A long-standing peculiarity in Russian president Vladimir Putin's walk — with his right arm held almost immobile, while his left arm swings freely — has sparked speculation over the years about its origins, with rumors ranging from an in-utero stroke to a childhood bout with polio. Now, a new study by a group of neurologists reaches a very different conclusion, pinning the source of Putin's gait on the training he received while he was in the Soviet Union's KGB, the nation's national security agency. In the study, published online today (Dec. 14) in the journal The BMJ, the researchers discovered that several other prominent Russian officials displayed a similar gait, which they say could also be linked to KGB training intended to keep a man's "gun arm" close to his holster, ready to draw a weapon at a moment's notice. [Top 10 Ailing US Presidents] When most of us walk, we naturally swing our arms at our sides in opposition to our legs' movements — and we do it without even thinking about it. Scientists have questioned whether swinging our arms actually benefits the way we move, and some studies have concluded that arm swinging in runners helps to maintain balance and conserve energy. But swinging only one arm is unusual, said Bastiaan R. Bloem, a co-author of the new study and professor of movement disorder neurology at Radboud University Nijmegen Medical Centre in the Netherlands. In fact, an immobile arm is one of the earliest known indicators of Parkinson's disease, he said. After a colleague sent Bloem an email about a YouTube video showing Putin's stiff right arm, Bloem was intrigued enough to dig a little deeper, he told Live Science. He found a number of videos showing Putin at public events where he walked for long distances. The lack of arm movement had persisted across years. "You could say, if it were one occasion, maybe he just had a painful shoulder or some other intermittent problem," Bloem said. "But then we discovered this was a consistent finding stretching out over a period of multiple years." Bloem and a number of his colleagues practice a subdiscipline of neurology that identifies them as "movement disorder enthusiasts." As the term suggests, analyzing how people walk is second nature to these specialists — at neurology conferences, they're the ones evaluating how everyone else ambles across the room. "Normal movements are complex, and then seeing how they go wrong, when there are defects in the brain, is a fascinating area," Bloem said. Footage of Putin's walk intrigued Bloem and the study co-authors. But it didn't take long for them to rule out Parkinson's as a cause for Putin's unusual gait. Parkinson's is a progressive disease, and in footage separated by years, there was no evidence that the movement of Putin's arm, or of any other part of his body, was getting progressively worse. In fact, all evidence seemed to indicate that overall, Putin is in fine physical shape. The researchers evaluated footage of Putin performing a number of different activities, and pronounced his motor skills "excellent." It was then that Bloem discovered that Putin wasn't the only Russian official walking this way. The researchers observed similar walking patterns — a stiff, nearly immobile right arm accompanying otherwise normal movement — in four other prominent Russian officials: Prime Minister Dmitry Medvedev; former Minister of Defense Anatoly Serdyukov; Sergei Ivanov, chief of the presidential administration of Russia; and Commander of the Western Military District Anatoly Sidarov. Other footage and photographs that the scientists examined showed that the Russian officials were all right-handed and did not appear to suffer from any impairment of their right arms, except as exhibited while they were walking. That, Bloem told Live Science, was when things became "reallypeculiar." The odds of all five Russian officials suffering from Parkinson's and exhibiting precisely the same symptoms that appeared on the same side of the body and at the same stage of degeneration were slim. Bloem and his colleagues knew there had to be another explanation, and they found it — not in medical literature, but in the pages of a KGB training manual. [3 Myths About Parkinson's Disease] "It literally says, when you're walking, don't move the right arm, keep it close to the holster and be ready to draw the gun," Bloem described. Putin and Ivanov both served in the KGB, where they would have doubtless been trained "by the book," to restrict their right arm movements while walking. And although the other officials were not KGB, their military backgrounds could explain their adopting this particular gait. For Medvedev, the only official with neither KGB nor military training, the study suggests that his reduced arm swing could be an example of "imitating the boss," a practice not uncommon in Russia, where officials frequently absorb mannerisms of their superiors, according to the researchers. The study authors found more examples of this weapon-ready walk in another unlikely location — Hollywood movies about rough-and-ready "wild west" gunfighters. Like the Russian officials, actors portraying gunslingers in old-time westerns displayed a similarly immobile right arm when they strode down Main Street at high noon. The researchers concluded that although Putin's movements appear to be the result of conditioning, and not an example of a neurological disorder, the study is still valuable to those who study diseases like Parkinson's, Bloem said. By drawing attention to this trait as a symptom of Parkinson's, the new study could help doctors identify Parkinson's earlier, and prevent the full-blown disease from developing. And reporting it with a touch of whimsy doesn't hurt either, Bloem added. "It's a tongue-in-cheek, semi-funny paper, but there's a very serious message behind it as well," Bloem said. "Teaching moments tend to stick best if they're presented in a humorous way." Follow Mindy Weisberger on Twitter and Google+. Follow us @livescience, Facebook & Google+. Original article on Live Science. 6 Politicians Who Got the Science Wrong Copyright 2015 LiveScience, a Purch company. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

Garzelli M.V.,University of Granada | Malamos I.,Radboud University Nijmegen
European Physical Journal C | Year: 2011

The analytical package written in FORM presented in this paper allows the computation of the complete set of Feynman Rules producing the Rational terms of kind R2 contributing to the virtual part of NLO corrections in the Standard Model of the Electroweak interactions. Building block topologies filled by means of generic scalars, vectors and fermions, allowing to build these Feynman Rules in terms of specific elementary particles, are explicitly given in the Rξ gauge class, together with the automatic dressing procedure to obtain the Feynman Rules from them. The results in more specific gauges, like the ’t Hooft Feynman one, follow as particular cases, in both the HV and the FDH dimensional regularization schemes. As a check on our formulas, the gauge independence of the total Rational contribution (R1+R2) to renormalized S-matrix elements is verified by considering the specific example of the H → γγ decay process at 1-loop. This package can be of interest for people aiming at a better understanding of the nature of the Rational terms. It is organized in a modular way, allowing a further use of some its files even in different contexts. Furthermore, it can be considered as a first seed in the effort towards a complete automation of the process of the analytical calculation of the R2 effective vertices, given the Lagrangian of a generic gauge theory of particle interactions. © 2011, The Author(s).

Meyer F.,University of Strasbourg | Meyer F.,Radboud University Nijmegen | Louilot A.,University of Strasbourg
Neuropsychopharmacology | Year: 2012

Growing evidence suggests schizophrenia may arise from abnormalities in early brain development. The prefrontal cortex (PFC) stands out as one of the main regions affected in schizophrenia. Latent inhibition, an interesting cognitive marker for schizophrenia, has been found in some studies to be reduced in acute patients. It is generally widely accepted that there is a dopaminergic dysfunctioning in schizophrenia. Moreover, several authors have reported that the psychostimulant, D-amphetamine (D-AMP), exacerbates symptoms in patients with schizophrenia. We explored in rats the effects in adulthood of neonatal transient inactivation of the PFC on behavioral and neurochemical anomalies associated with schizophrenia. Following tetrodotoxin (TTX) inactivation of the left PFC at postnatal day 8, latent inhibition-related dopaminergic responses and dopaminergic reactivity to D-AMP were monitored using in vivo voltammetry in the left core part of the nucleus accumbens in adult freely moving rats. Dopaminergic responses and behavioral responses were followed in parallel. Prefrontal neonatal inactivation resulted in disrupted behavioral responses of latent inhibition and latent inhibition-related dopaminergic responses in the core subregion. After D-AMP challenge, the highest dose (1.5 mg/kg i.p.) induced a greater dopamine increase in the core in rats microinjected with TTX, and a parallel increase in locomotor activity, suggesting that following prefrontal neonatal TTX inactivation animals display a greater behavioral and dopaminergic reactivity to D-AMP. Transitory inactivation of the PFC early in the postnatal developmental period leads to behavioral and neurochemical changes in adulthood that are meaningful for schizophrenia modeling. The data obtained may help our understanding of the pathophysiology of this disabling disorder. © 2012 American College of Neuropsychopharmacology. All rights reserved.

Jeong M.G.,Ulsan National Institute of Science and Technology | Van Hest J.C.M.,Radboud University Nijmegen | Kim K.T.,Ulsan National Institute of Science and Technology
Chemical Communications | Year: 2012

Block copolymers built on a dendritic block having fixed molecular weight but different number of peripheral PEG chains were synthesised. At a fixed block ratio, these block copolymers exhibited topological transition of cylindrical micelles depending on the number of PEG chains. © 2012 The Royal Society of Chemistry.

Den Hollander A.I.,Radboud University Nijmegen | Black A.,University of Pennsylvania | Bennett J.,University of Pennsylvania | Cremers F.P.M.,Radboud University Nijmegen
Journal of Clinical Investigation | Year: 2010

Nonsyndromic recessive retinal dystrophies cause severe visual impairment due to the death of photoreceptor and retinal pigment epithelium cells. These diseases until recently have been considered to be incurable. Molecular genetic studies in the last two decades have revealed the underlying molecular causes in approximately two-thirds of patients. The mammalian eye has been at the forefront of therapeutic trials based on gene augmentation in humans with an early-onset nonsyndromic recessive retinal dystrophy due to mutations in the retinal pigment epithelium-specific protein 65kDa (RPE65) gene. Tremendous challenges still lie ahead to extrapolate these studies to other retinal disease-causing genes, as human gene augmentation studies require testing in animal models for each individual gene and sufficiently large patient cohorts for clinical trials remain to be identified through cost-effective mutation screening protocols.

Nutt J.G.,Oregon Health And Science University | Bloem B.R.,Radboud University Nijmegen | Giladi N.,Tel Aviv University | Hallett M.,U.S. National Institutes of Health | And 2 more authors.
The Lancet Neurology | Year: 2011

Freezing of gait (FoG) is a unique and disabling clinical phenomenon characterised by brief episodes of inability to step or by extremely short steps that typically occur on initiating gait or on turning while walking. Patients with FoG, which is a feature of parkinsonian syndromes, show variability in gait metrics between FoG episodes and a substantial reduction in step length with frequent trembling of the legs during FoG episodes. Physiological, functional imaging, and clinical-pathological studies point to disturbances in frontal cortical regions, the basal ganglia, and the midbrain locomotor region as the probable origins of FoG. Medications, deep brain stimulation, and rehabilitation techniques can alleviate symptoms of FoG in some patients, but these treatments lack efficacy in patients with advanced FoG. A better understanding of the phenomenon is needed to aid the development of effective therapeutic strategies. © 2011 Elsevier Ltd.

Dmitrienko V.E.,RAS Shubnikov Institute of Crystallography | Ovchinnikova E.N.,Moscow State University | Collins S.P.,Diamond Light Source | Nisbet G.,Diamond Light Source | And 5 more authors.
Nature Physics | Year: 2014

Magnetism - the spontaneous alignment of atomic moments in a material - is driven by quantum mechanical exchange interactions that operate over interatomic distances. Some magnetic interactions cause, or are caused by, a twisting of arrangements of atoms. This can lead to the magnetoelectric effect, predicted to play a prominent role in future technology, and to the phenomenon of weak ferromagnetism, governed by the so-called Dzyaloshinskii-Moriya interaction. Here we determine the sign of the latter interaction in iron borate (FeBO 3) by using synchrotron radiation. We present a novel experimental technique based on the interference between two X-ray scattering processes, where one acts as a reference wave. Our experimental results are validated by state-of-the-art ab initio calculations. Together, our experimental and theoretical approaches are expected to open up new possibilities for exploring, modelling and exploiting novel magnetic and magnetoelectric materials. © 2014 Macmillan Publishers Limited.

Witjes J.A.,Radboud University Nijmegen | Comperat E.,Groupe Hospitalier Pitie Salpetriere | Cowan N.C.,Manor Hospital | De Santis M.,ACR ITR | And 5 more authors.
European Urology | Year: 2014

Context The European Association of Urology (EAU) guidelines panel on Muscle-invasive and Metastatic bladder cancer (BCa) updates its guidelines yearly. This updated summary provides a synthesis of the 2013 guidelines document, with emphasis on the latest developments. Objective To provide graded recommendations on the diagnosis and treatment of patients with muscle-invasive BCa (MIBC), linked to a level of evidence. Evidence acquisition For each section of the guidelines, comprehensive literature searches covering the past 10 yr in several databases were conducted, scanned, reviewed, and discussed both within the panel and with external experts. The final results are reflected in the recommendations provided. Evidence synthesis Smoking and work-related carcinogens remain the most important risk factors for BCa. Computed tomography (CT) and magnetic resonance imaging can be used for staging, although CT is preferred for pulmonary evaluation. Open radical cystectomy with an extended lymph node dissection (LND) remains the treatment of choice for treatment failures in non-MIBC and T2-T4aN0M0 BCa. For well-informed, well-selected, and compliant patients, however, multimodality treatment could be offered as an alternative, especially if cystectomy is not an option. Comorbidity, not age, should be used when deciding on radical cystectomy. Patients should be encouraged to actively participate in the decision-making process, and a continent urinary diversion should be offered to all patients unless there are specific contraindications. For fit patients, cisplatinum-based neoadjuvant chemotherapy should always be discussed, since it improves overall survival. For patients with metastatic disease, cisplatin-containing combination chemotherapy is recommended. For unfit patients, carboplatin combination chemotherapy or single agents can be used. Conclusions This 2013 EAU Muscle-invasive and Metastatic BCa guidelines updated summary aims to increase the quality of care and outcome for patients with muscle-invasive or metastatic BCa. Patient summary In this paper we update the EAU guidelines on Muscle-invasive and Metastatic bladder cancer. We recommend that chemotherapy be administered before radical treatment and that bladder removal be the standard of care for disease confined to the bladder. © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Zickermann V.,Goethe University Frankfurt | Wirth C.,Albert Ludwigs University of Freiburg | Nasiri H.,University of Cambridge | Nasiri H.,Institute of Organic Chemistry and Chemical Biology | And 6 more authors.
Science | Year: 2015

Proton-pumping complex I of the mitochondrial respiratory chain is among the largest and most complicated membrane protein complexes. The enzyme contributes substantially to oxidative energy conversion in eukaryotic cells. Its malfunctions are implicated in many hereditary and degenerative disorders. We report the x-ray structure of mitochondrial complex I at a resolution of 3.6 to 3.9 angstroms, describing in detail the central subunits that execute the bioenergetic function. A continuous axis of basic and acidic residues running centrally through the membrane arm connects the ubiquinone reduction site in the hydrophilic arm to four putative proton-pumping units. The binding position for a substrate analogous inhibitor and blockage of the predicted ubiquinone binding site provide a model for the "deactive" form of the enzyme. The proposed transition into the active form is based on a concerted structural rearrangement at the ubiquinone reduction site, providing support for a two-state stabilization-change mechanism of proton pumping.

Farquhar J.,Radboud University Nijmegen | Hill N.J.,New York State Department of Health
Neuroinformatics | Year: 2013

Detecting event related potentials (ERPs) from single trials is critical to the operation of many stimulus-driven brain computer interface (BCI) systems. The low strength of the ERP signal compared to the noise (due to artifacts and BCI irrelevant brain processes) makes this a challenging signal detection problem. Previous work has tended to focus on how best to detect a single ERP type (such as the visual oddball response). However, the underlying ERP detection problem is essentially the same regardless of stimulus modality (e.g. visual or tactile), ERP component (e.g. P300 oddball response, or the error-potential), measurement system or electrode layout. To investigate whether a single ERP detection method might work for a wider range of ERP BCIs we compare detection performance over a large corpus of more than 50 ERP BCI datasets whilst systematically varying the electrode montage, spectral filter, spatial filter and classifier training methods. We identify an interesting interaction between spatial whitening and regularised classification which made detection performance independent of the choice of spectral filter low-pass frequency. Our results show that pipeline consisting of spectral filtering, spatial whitening, and regularised classification gives near maximal performance in all cases. Importantly, this pipeline is simple to implement and completely automatic with no expert feature selection or parameter tuning required. Thus, we recommend this combination as a "best-practice" method for ERP detection problems. © 2012 Springer Science+Business Media New York.

Doherty K.M.,University College London | van de Warrenburg B.P.,Radboud University Nijmegen | Peralta M.C.,Cesar Milstein Hospital | Silveira-Moriyama L.,University College London | And 3 more authors.
The Lancet Neurology | Year: 2011

Postural deformities are frequent and disabling complications of Parkinson's disease (PD) and atypical parkinsonism. These deformities include camptocormia, antecollis, Pisa syndrome, and scoliosis. Recognition of specific postural syndromes might have differential diagnostic value in patients presenting with parkinsonism. The evidence to date suggests that postural deformities have a multifactorial pathophysiology. Contributing factors include muscular rigidity; axial dystonia; weakness caused by myopathy; body scheme defects due to centrally impaired proprioception; and structural changes in the spine. The relative contribution of these different factors varies between patients and across specific syndromes. Improved understanding of the mechanisms underlying postural deformities in PD might ultimately lead us to more effective management strategies for these disabling and drug-refractory complications. © 2011 Elsevier Ltd.

van der Meij R.,Radboud University Nijmegen | Kahana M.,University of Pennsylvania | Maris E.,Radboud University Nijmegen
Journal of Neuroscience | Year: 2012

Spatially distributed phase-amplitude coupling (PAC) is a possible mechanism for selectively routing information through neuronal networks. If so, two key properties determine its selectivity and flexibility, phase diversity over space, and frequency diversity. To investigate these issues, we analyzed 42 human electrocorticographic recordings from 27 patients performing a working memory task. Wedemonstrate that (1) spatially distributed PAC occurred at distances >10 cm, (2) involved diverse preferred coupling phases, and (3) involved diverse frequencies. Using a novel technique [N-way decomposition based on the PARAFAC (for Parallel Factor analysis) model], we demonstrate that (4) these diverse phases originated mainly from the phase-providing oscillations. With these properties, PAC can be the backbone of a mechanism that is able to separate spatially distributed networks operating in parallel. © 2012 the authors.

van der Kolk N.M.,Radboud University Nijmegen | King L.A.,Oregon Health And Science University
Movement Disorders | Year: 2013

Parkinson's disease is a prevalent neurodegenerative disorder for which only symptomatic treatment exists. Gait and balance disturbance is common in Parkinson's disease and is a major contributor to increased disability and decreased health-related quality of life and survival. Balance and gait deficits in Parkinson's disease are notoriously difficult to treat and are not significantly helped by pharmacological or surgical treatment. The last two decades have seen a dramatic increase in the research and clinical interest in using exercise as a treatment for mobility problems in people with Parkinson's disease. With exciting advances in basic science research suggesting neurochemical and neuroplastic changes after exercise, an increasing number of high-quality studies are documenting particular aspects of mobility improving after exercise. Exercise has the potential to help both motor (gait, balance, strength) and nonmotor (depression, apathy, fatigue, constipation) aspects of Parkinson's disease as well as secondary complications of immobility (cardiovascular, osteoporosis). This perspective article focuses primarily on recent evidence on the effects of exercise in improving mobility while highlighting the importance of targeted exercise intervention for maximizing the benefits of exercise. Suggestions for exercise guidelines, adherence issues, and directions for future research are provided. © 2013 Movement Disorder Society.

Cavalli G.,San Raffaele Scientific Institute | Dinarello C.A.,Radboud University Nijmegen
Rheumatology (Oxford, England) | Year: 2015

The inflammatory cytokines IL-1α and IL-1β orchestrate local and systemic inflammatory responses underlying a broad spectrum of diseases. Three agents for reducing IL-1 activities are currently available. Anakinra is a recombinant form of the naturally occurring IL-1 receptor antagonist. Anakinra binds to the IL-1 receptor and prevents the activity of IL-1α and IL-1β. The soluble decoy receptor rilonacept and the neutralizing mAb canakinumab block IL-1β. A mAb directed against the IL-1 receptor and a neutralizing anti-human IL-1α are in clinical trials. The availability of therapies specifically targeting IL-1 unveiled the pathological role of IL-1-mediated inflammation in a broadening list of diseases. Conditions effectively treated with agents blocking IL-1 range from classic rheumatic diseases, such as RA and gout, to autoinflammatory syndromes, such as systemic JIA and FMF. However, IL-1 antagonism is also effective against highly prevalent inflammatory diseases, namely cardiovascular diseases and type 2 diabetes, conditions that are frequently encountered as co-morbidities in patients with rheumatic diseases. Thereby, IL-1 inhibition has the potential to lift the burden of disease for patients with rheumatic conditions, but also to provide clinical benefits beyond the efficacy on osteoarticular manifestations. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email:

Nutt J.G.,Oregon Health And Science University | Horak F.B.,Oregon Health And Science University | Bloem B.R.,Radboud University Nijmegen
Movement Disorders | Year: 2011

Gait, balance, and falls have become increasingly common topics of published articles in the Movement Disorders journal since its launch in 1986. This growth represents an increasing awareness of the importance of mobility to patients' quality of life. New methods have become available that allow for accurate measurement of many aspects for gait and balance. This has led to new concepts of understanding gait and balance disorders. Neuroimaging has begun to reveal the neural circuitry underlying gait and balance. The physiology and pathophysiology of balance and gait are beginning to tease out the many processes involved in mobility and how they may be disrupted by disease processes. With these advances, the old therapeutic nihilism that characterized the clinician's approach to falls and gait disorders is disappearing, as innovative physiotherapy, exercise, drugs, and deep brain stimulation are being employed for gait and balance disorders. © 2011 Movement Disorder Society.

Oosterwijk E.,Radboud University Nijmegen | Gillies R.J.,Moffitt Cancer Center
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

Themetabolism of cancer cells differs substantially from normal cells, including ion transport. Although this phenomenon has been long recognized, ion transporters have not been viewed as suitable therapeutic targets. However, the acidic pH values present in tumours which are well outside of normal limits are now becoming recognized as an important therapeutic target. Carbonic anhydrase IX (CAIX) is fundamental to tumour pH regulation. CAIX is commonly expressed in cancer, but lowly expressed in normal tissues and that presents an attractive target. Here, we discuss the possibilities of exploiting the acidic, hypoxic tumour environment as possible target for therapy. Additionally, clinical experience with CAIX targeting in cancer patients is discussed. © 2014 The Author(s) Published by the Royal Society.

Jacquemyn H.,Catholic University of Leuven | Brys R.,Research Institute for Nature and Forest | Jongejans E.,Radboud University Nijmegen
Journal of Ecology | Year: 2010

1. In woodland herbs, the probability of flowering and costs associated with reproduction may strongly depend on environmental context (shade vs. light habitats) and on plant size. This may be particularly true for tuberous orchids that inhabit woodlands, as the amount of incoming radiation and total leaf area strongly determine photosynthetic capacity and hence the amount of carbohydrates that can be relocated to below-ground storage organs that form next year's rosette and flowering stalk. 2. To fully comprehend the impact of size-dependent reproduction on population dynamics under varying light conditions, life cycle models should therefore include plant size in a continuous manner. In this study, annual changes in plant size and demographic behaviour of the tuberous perennial orchid Orchis purpurea were monitored during seven consecutive years (2003-2009) in open and shaded woodland. Integral projection models (IPMs) and life table response experiments (LTRE) were used to investigate the extent to which variation in plant size affected the overall population dynamics of this species and to decompose differences in population growth rates between populations of open and shaded woodland into contributions from growth, survival and reproduction. 3. Both plants in shaded and light environments needed to be a certain size to initiate flowering, but this threshold size was almost three times as large in shaded environments as in light environments. Plants in open woodlands flowered more frequently over the years, showed less size regression after flowering and produced significantly more fruits than plants in shaded environments, resulting in significantly larger population growth rates. 4. Our life cycle models revealed that costs of reproduction, measured at the population-level, were small in the light environment, and more than buffered by the increase in survival of flowering plants compared to non-flowering plants. In the shade environment, however, the costs of reproduction were significant and made the difference between a stable (current) and a growing (without reproduction costs) population. 5. Synthesis. Light penetration to the soil is a key variable determining population dynamics of woodland orchids. Our analyses show that differences in vital rates related to size-dependent reproduction (flowering) and growth are essential drivers of changes in orchid population dynamics in different light environments. The combination of IPMs and LTREs thus proves to be very useful when studying the fitness consequences of size- and context-dependent phenomena like flowering strategies and costs of reproduction. © 2010 The Authors. Journal compilation © 2010 British Ecological Society.

Koenders P.G.,Beter Occupational and Health Services | Van Strien T.,Radboud University Nijmegen
Journal of Occupational and Environmental Medicine | Year: 2011

Objective: To examine the associations between the lifestyle factors-sports, alcohol, nutrition, overweight, and smoking, the eating styles of dietary restraint, external eating, and emotional eating on the one hand, and the change in body mass index (BMI) on the other hand. METHODS: Using a Web-based lifestyle questionnaire, responses were obtained from 1562 employees. RESULTS: We found a consistent main effect of emotional eating and doing sports on change in BMI. High emotional eating was related to weight gain, whereas a high level of sporting was related to weight loss. Restrained eating and external eating were not found to have a significant influence on change in BMI. Additionally, a consistent moderator effect of sporting on emotional eating was found (P < .05). The association between BMI change and emotional eating was less strong for employees with high engagement in strenuous sports compared with those with low engagement in strenuous sports. This indicates that strenuous physical activity can indeed attenuate the positive association between emotional eating and body weight gain. CONCLUSION: Emotions may drive people with overweight and obesity to overeat. Sports activities may attenuate but do not solve the problem. If we want to cure the disease, psychological treatment strategies have to be developed. Copyright © 2011 by American College of Occupational and Environmental Medicine.

Borgdorff M.W.,Public Health Service Amsterdam | Borgdorff M.W.,University of Amsterdam | van Soolingen D.,National Institute for Public Health and the Environment RIVM | van Soolingen D.,Radboud University Nijmegen
Clinical Microbiology and Infection | Year: 2013

Tuberculosis (TB) has re-emerged over the past two decades: in industrialized countries in association with immigration, and in Africa owing to the human immunodeficiency virus epidemic. Drug-resistant TB is a major threat worldwide. The variable and uncertain impact of TB control necessitates not only better tools (diagnostics, drugs, and vaccines), but also better insights into the natural history and epidemiology of TB. Molecular epidemiological studies over the last two decades have contributed to such insights by answering long-standing questions, such as the proportion of cases attributable to recent transmission, risk factors for recent transmission, the occurrence of multiple Mycobacterium tuberculosis infection, and the proportion of recurrent TB cases attributable to re-infection. M. tuberculosis lineages have been identified and shown to be associated with geographical origin. The Beijing genotype is strongly associated with multidrug resistance, and may have escaped from bacille Calmette-Guérin-induced immunity. DNA fingerprinting has quantified the importance of institutional transmission and laboratory cross-contamination, and has helped to focus contact investigations. Questions to be answered in the near future with whole genome sequencing include identification of chains of transmission within clusters of patients, more precise quantification of mixed infection, and transmission probabilities and rates of progression from infection to disease of various M. tuberculosis lineages, as well as possible variations in vaccine efficacy by lineage. Perhaps most importantly, dynamics in the population structure of M. tuberculosis in response to control measures in high-prevalence areas should be better understood. © 2013 European Society of Clinical Microbiology and Infectious Diseases.

Hendriks W.J.A.J.,Radboud University Nijmegen | Pulido R.,BioCruces Health Research Institute | Pulido R.,Ikerbasque
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2013

Reversible tyrosine phosphorylation of proteins is a key regulatory mechanism to steer normal development and physiological functioning of multicellular organisms. Phosphotyrosine dephosphorylation is exerted by members of the super-family of protein tyrosine phosphatase (PTP) enzymes and many play such essential roles that a wide variety of hereditary disorders and disease susceptibilities in man are caused by PTP alleles. More than two decades of PTP research has resulted in a collection of PTP genetic variants with corresponding consequences at the molecular, cellular and physiological level. Here we present a comprehensive overview of these PTP gene variants that have been linked to disease states in man. Although the findings have direct bearing for disease diagnostics and for research on disease etiology, more work is necessary to translate this into therapies that alleviate the burden of these hereditary disorders and disease susceptibilities in man. © 2013 The Authors.

Jacquemyn H.,Catholic University of Leuven | de Meester L.,Charles University | Jongejans E.,Radboud University Nijmegen | Honnay O.,Catholic University of Leuven
Journal of Ecology | Year: 2012

1. The effects of habitat fragmentation on plant population genetic structure and diversity are relatively well studied. Yet, most of these studies used molecular tools focusing on neutral genetic markers, and much less is known about the potential evolutionary consequences of habitat fragmentation on ecologically relevant plant traits. 2. It can be expected that the altered biotic and abiotic conditions and limited gene flow following habitat fragmentation may impose strong selection pressures on traits important for plant fitness. Responses to these selection pressures may, however, be hampered by reduced genetic diversity through genetic drift. Conversely, evolutionary changes in flower or dispersal traits may itself impact the strength of inbreeding and genetic drift. 3. In this review, we highlight different reproductive plant traits that may be under selection following habitat fragmentation, and we examine studies that have shown indications for rapid evolutionary responses. 4. There are still relatively few studies that have convincingly shown that habitat fragmentation generates rapid evolutionary responses. Separating genetic from plastic trait responses and quantifying the long-term fitness consequences of evolutionary changes in plant traits also remain major challenges. 5. Synthesis. Many plant traits may be subject to selection following habitat fragmentation, but, until now, studies that quantified evolutionary responses to habitat fragmentation are limited. To study the consequences of changing plant traits for population fitness, we advocate applying population models that link demographic vital rates, the responding plant traits and their heritability. © 2012 The Authors. Journal of Ecology © 2012 British Ecological Society.

de Gouw D.,Radboud University Nijmegen | Diavatopoulos D.A.,Radboud University Nijmegen | Bootsma H.J.,Radboud University Nijmegen | Hermans P.W.,Radboud University Nijmegen | Mooi F.R.,National Institute for Public Health and the Environment RIVM
FEMS Microbiology Reviews | Year: 2011

Pertussis, or whooping cough, is a highly contagious, acute respiratory disease of humans that is caused by the Gram-negative bacterial pathogen Bordetella pertussis. In the face of extensive global vaccination, this extremely monomorphic pathogen has persisted and re-emerged, causing approximately 300000 deaths each year. In this review, we discuss the interaction of B. pertussis with the host mucosal epithelium and immune system. Using a large number of virulence factors, B. pertussis is able to create a niche for colonization in the human respiratory tract. The successful persistence of this pathogen is mainly due to its ability to interfere with almost every aspect of the immune system, from the inhibition of complement- and phagocyte-mediated killing to the suppression of T- and B-cell responses. Based on these insights, we delineate ideas for the rational design of improved vaccines that can target the 'weak spots' in the pathogenesis of this highly successful pathogen. © 2011 RIVM. FEMS Microbiology Reviews © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd.

Teunisse R.J.,Locatie Brinkgreven | Rikkert M.G.M.O.,Radboud University Nijmegen
American Journal of Geriatric Psychiatry | Year: 2012

Objective: To assess the prevalence of musical hallucinations in patients referred for audiometric testing and to analyze associations with age, sex, degree of hearing loss, asymmetrical hearing loss, and tinnitus. Methods: Patients referred for audiometric testing underwent a semi-structured interview on tinnitus and musical hallucinations. Results: Out of 194 patients, most of whom had mild to moderate hearing loss, seven (3.6%) had musical hallucinations. Significant associations were found with female sex and predominant left-sided hearing impairment, but not with age, severity of hearing loss, or tinnitus. Conclusion: This study offers no evidence that age is a risk factor. Musical hallucinations seem to be prevalent in women with predominant left-sided hearing impairment. © 2012 American Association for Geriatric Psychiatry.

BERKELEY, Calif. and OSS, The Netherlands, Dec. 06, 2016 (GLOBE NEWSWIRE) -- Aduro Biotech, Inc. (Nasdaq:ADRO), a biopharmaceutical company with three distinct immunotherapy technologies, announced today that Hans van Eenennaam, Ph.D., chief operational officer and executive director of Aduro Biotech Europe, and John Dulos, Ph.D., principal scientist, will be honored tonight by the Intellectual Property Owners Education Foundation (IPOEF) as winners of the 43rd Inventor of the Year Award for their work relating to the discovery of KEYTRUDA® (pembrolizumab). KEYTRUDA is marketed by Merck & Co., Inc., Kenilworth, NJ, USA (known as MSD outside the U.S. and Canada) and is the first FDA-approved PD-1 inhibitor for the treatment of select cancers. “It is an honor to have been part of the team whose work led to the discovery of KEYTRUDA and positively impacted the lives of many cancer patients,” said Dr. van Eenennaam. “Now as part of Aduro Biotech Europe, where we are focused on developing novel B-select antibodies to modulate the immune system, we are pleased to be collaborating once again with the MSD team on what we believe to be the best-in-class anti-CD27 therapeutic antibody.” Dr. Dulos, principal scientist and project team lead for Aduro’s anti-APRIL BION-1301 program, commented, “As a scientist, it is incredibly satisfying to have been part of a team whose discoveries today are having a meaningful impact on the lives of many patients with several cancer types.  We thank the Intellectual Property Owners Education Foundation for this honor and will continue to leverage our knowledge and discoveries in the field of immuno-oncology with the aim of helping cancer patients in need.” Hans van Eenennaam, Ph.D., a chemist by training, has nearly 15 years of experience in the pharmaceutical and biotechnology industry and in-depth expertise in the field of immunology.  He currently serves as chief operational officer and executive director of Aduro Biotech Europe, where he leads the development of new anti-cancer antibodies using the company’s proprietary B-select antibody technology.  Prior to its acquisition by Aduro in 2015, Dr. van Eenennaam served as chief operational officer of BioNovion, a company he co-founded in 2011 to focus on the development of innovative therapeutic antibodies in the field of immuno-oncology.  He is named as inventor on seven pending and granted patent families, including the patents for KEYTRUDA, and an author on over 25 publications.  Dr. van Eenennaam received his doctorate in autoimmune biochemistry (cum laude) from Radboud University Nijmegen, the Netherlands. John Dulos, Ph.D., an immunologist with more than 20 years of experience in the pharmaceutical and biotechnology industry, is a leader in the field of immunology, oncology and infectious diseases. He currently serves as principal scientist at Aduro Biotech Europe where he oversees research and development of the company’s proprietary anti-APRIL (A PRoliferation-Inducing Ligand)-targeting monoclonal antibody, BION-1301, for the treatment of multiple myeloma. Throughout his career at multiple companies, Dr. Dulos has applied his expertise in in vitro and in vivo pharmacology of small molecules, vaccines and antibodies from preclinical development through Phase 2 clinical studies.  He is named as an inventor on two patent applications relating to KEYTRUDA and an author on 16 peer-reviewed publications, including lead authorship on a 2012 paper that first described the immune stimulating activity of KEYTRUDA (Journal of Immunotherapy 35:169-78). Dr. Dulos received his doctorate from Utrecht University in the Netherlands. About the IPOEF Inventor of the Year Award Each year, the IPOEF recognizes outstanding recent inventions with its annual Inventor of the Year Award.  In 2016, the foundation is celebrating innovation that has led to breakthroughs in cancer treatment by honoring the inventors of six drugs in the field of immunotherapy oncology treatment, including Merck & Co.’s KEYTRUDA®.  To learn more about the IPOEF and this award, visit About the Aduro - MSD Collaboration BioNovion B.V. and MSD, through a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, entered into a worldwide license agreement in 2014 for the development and commercialization of CD27 antibody agonists, and BioNovion received an up-front payment of $15 million. In 2015, BioNovion was acquired by Aduro Biotech and became its subsidiary, Aduro Biotech Europe B.V. Under the agreement, a Joint Research Committee was formed to advance the program. Aduro has been reimbursed for certain research activities and is eligible to receive future development, commercial and net sales milestone payments. In addition, Aduro is eligible to receive royalties in the mid-single digits to low teens based on any net sales of the product, if it is approved for marketing. About Aduro Aduro Biotech, Inc. is an immunotherapy company focused on the discovery, development and commercialization of therapies that transform the treatment of challenging diseases. Aduro's technology platforms, which are designed to harness the body's natural immune system, are being investigated in cancer indications and have the potential to expand into autoimmune and infectious diseases. Aduro's LADD technology platform is based on proprietary attenuated strains of Listeria that have been engineered to express tumor-associated antigens to induce specific and targeted immune responses. This platform is being developed as a treatment for multiple indications, including pancreatic, ovarian, lung and prostate cancers, mesothelioma and glioblastoma. Additionally, a personalized form of LADD, or pLADD, is being developed utilizing tumor neoantigens that are specific to an individual patient’s tumor. Aduro's STING Pathway Activator platform is designed to activate the intracellular STING receptor, resulting in a potent tumor-specific immune response. ADU-S100 is the first STING Pathway Activator compound to enter the clinic and is currently being evaluated in a Phase 1 study in patients with cutaneously accessible metastatic solid tumors or lymphomas. Aduro’s B-select monoclonal antibody platform includes a number of immune modulating assets in research and preclinical development. Aduro is collaborating with leading global pharmaceutical companies to expand its products and technology platforms. For more information, please visit This press release contains forward-looking statements for purposes of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include statements regarding our intentions or current expectations concerning, among other things, the potential for our technology platforms, plans, and the potential for eventual regulatory approval of our product candidates. In some cases, you can identify these statements by forward-looking words such as “may,” “will,” “continue,” “anticipate,” “intend,” “could,” “project,” “expect” or the negative or plural of these words or similar expressions.  Forward-looking statements are not guarantees of future performance and are subject to risks and uncertainties that could cause actual results and events to differ materially from those anticipated, including, but not limited to, our history of net operating losses and uncertainty regarding our ability to achieve profitability, our ability to develop and commercialize our product candidates, our ability to use and expand our technology platforms to build a pipeline of product candidates, our ability to obtain and maintain regulatory approval of our product candidates, our inability to operate in a competitive industry and compete successfully against competitors that have greater resources than we do, our reliance on third parties, and our ability to obtain and adequately protect intellectual property rights for our product candidates.  We discuss many of these risks in greater detail under the heading “Risk Factors” contained in our quarterly report on Form 10-Q for the quarter ended September 30, 2016, which is on file with the Securities and Exchange Commission. Any forward-looking statements that we make in this press release speak only as of the date of this press release. We assume no obligation to update our forward-looking statements whether as a result of new information, future events or otherwise, after the date of this press release.

Schulze H.-J.,National Institute of Nuclear Physics, Italy | Rijken T.,Radboud University Nijmegen
Physical Review C - Nuclear Physics | Year: 2011

We perform Brueckner-Hartree-Fock calculations of hypernuclear matter employing the recent Nijmegen ESC08 hyperon-nucleon potentials, provide useful parametrizations of the numerical results, and compute the structure of hyperon (neutron) stars within this approach. Very low maximum masses below 1.4 solar masses are found. © 2011 American Physical Society.

Voss T.S.,Swiss Tropical and Public Health Institute | Voss T.S.,University of Basel | Bozdech Z.,Nanyang Technological University | Bartfai R.,Radboud University Nijmegen
Current Opinion in Microbiology | Year: 2014

Malaria parasites run through a complex life cycle in the vertebrate host and mosquito vector. This not only requires tightly controlled mechanisms to govern stage-specific gene expression but also necessitates effective strategies for survival under changing environmental conditions. In recent years, the combination of different -omics approaches and targeted functional studies highlighted that Plasmodium falciparum blood stage parasites use heterochromatin-based gene silencing as a unifying strategy for clonally variant expression of hundreds of genes. In this article, we describe the epigenetic control mechanisms that mediate alternative expression states of genes involved in antigenic variation, nutrient uptake and sexual conversion and discuss the relevance of this strategy for the survival and transmission of malaria parasites. © 2014.

Falcke H.,Radboud University Nijmegen | Falcke H.,Max Planck Institute for Radio Astronomy | Rezzolla L.,Max Planck Institute For Gravitationsphysik | Rezzolla L.,Institute For Theoretische Physik
Astronomy and Astrophysics | Year: 2014

Context. Several fast radio bursts have been discovered recently, showing a bright, highly dispersed millisecond radio pulse. The pulses do not repeat and are not associated with a known pulsar or gamma-ray burst. The high dispersion suggests sources at cosmological distances, hence implying an extremely high radio luminosity, far larger than the power of single pulses from a pulsar. Aims. We suggest that a fast radio burst represents the final signal of a supramassive rotating neutron star that collapses to a black hole due to magnetic braking. The neutron star is initially above the critical mass for non-rotating models and is supported by rapid rotation. As magnetic braking constantly reduces the spin, the neutron star will suddenly collapse to a black hole several thousand to million years after its birth. Methods. We discuss several formation scenarios for supramassive neutron stars and estimate the possible observational signatures making use of the results of recent numerical general-relativistic calculations. Results. While the collapse will hide the stellar surface behind an event horizon, the magnetic-field lines will snap violently. This can turn an almost ordinary pulsar into a bright radio "blitzar": accelerated electrons from the travelling magnetic shock dissipate a significant fraction of the magnetosphere and produce a massive radio burst that is observable out to z > 0.7. Only a few per cent of the neutron stars need to be supramassive in order to explain the observed rate. Conclusions. We suggest the intriguing possibility that fast radio bursts might trace the solitary and almost silent formation of stellar mass black holes at high redshifts. These bursts could be an electromagnetic complement to gravitational-wave emission and reveal a new formation and evolutionary channel for black holes and neutron stars that are not seen as gamma-ray bursts. If supramassive neutron stars are formed at birth and not by accretion, radio observations of these bursts could trace the core-collapse supernova rate throughout the universe. © 2014 ESO.

Brandt A.J.,Case Western Reserve University | De Kroon H.,Radboud University Nijmegen | Reynolds H.L.,Indiana University Bloomington | Burns J.H.,Case Western Reserve University
Journal of Ecology | Year: 2013

Most studies of soil heterogeneity have focused on underlying abiotic factors such as soil nutrients. However, increasing recognition of plant-soil feedback (PSF) effects on plant growth, combined with the observation that PSFs operate at small spatial scales, suggests that heterogeneity due to PSF could affect plant population and community dynamics. The consequences of PSF-generated heterogeneity for coexistence depend on heterogeneity's effects on vital rates and how those vital rates influence population-level recruitment dynamics. We measured vital rates and recruitment dynamics of three congeneric pairs of introduced perennial plants grown as monocultures in experimental PSF-generated soil environments. Field soils collected from conspecifics and congeners were alternated in patches or mixed together to produce heterogeneous and homogeneous soils, respectively. We quantified the effects of PSF-generated heterogeneity on germination and establishment and determined how these vital rates affected recruitment. We calculated net pairwise interaction coefficients to predict whether PSFs could mediate coexistence between congeners. Soil heterogeneity altered the relationship of vital rates to recruitment dynamics for some species. For example, Solanum dulcamara recruited later into heterogeneous than homogeneous soils, and germination was a stronger predictor of the timing of recruitment in heterogeneous soil, while mortality was a stronger predictor in homogeneous soil. Contrasts between soils of different origin suggest that mixing soils had non-additive effects on vital rates (e.g. Rumex crispus mortality was higher in homogeneous than in conspecific or congener soil). Interaction coefficients predicted that PSFs in heterogeneous soils might mediate stable coexistence only of Rumex congeners. Synthesis. Heterogeneity generated by PSFs had species-specific effects on vital rates, with consequences for recruitment dynamics. Mixing soils of different origin often resulted in non-additive effects, which may indicate an interaction between soil abiotic and/or biotic properties and could predict non-additive responses to soil disturbance. Finally, quantifying the reciprocal effects of PSFs on congeners suggests that PSF-generated heterogeneity may promote coexistence of certain species, which was not evident from individual PSF responses. Future studies should determine whether such mechanisms might operate for more distantly related species. © 2013 The Authors. Journal of Ecology © 2013 British Ecological Society.

Szklarczyk R.,Maastricht University | Nooteboom M.,Radboud University Nijmegen | Osiewacz H.D.,Goethe University Frankfurt
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2014

Various molecular and cellular pathways are active in eukaryotes to control the quality and integrity of mitochondria. These pathways are involved in keeping a 'healthy' population of this essential organelle during the lifetime of the organism. Quality control (QC) systems counteract processes that lead to organellar dysfunction manifesting as degenerative diseases and ageing. We discuss disease- and ageing-related pathways involved in mitochondrial QC: mtDNA repair and reorganization, regeneration of oxidized amino acids, refolding and degradation of severely damaged proteins, degradation of whole mitochondria by mitophagy and finally programmed cell death. The control of the integrity of mtDNA and regulation of its expression is essential to remodel single proteins as well as mitochondrial complexes that determine mitochondrial functions. The redundancy of components, such as proteases, and the hierarchies of the QC raise questions about crosstalk between systems and their precise regulation. The understanding of the underlying mechanisms on the genomic, proteomic, organellar and cellular levels holds the key for the development of interventions for mitochondrial dysfunctions, degenerative processes, ageing and age-related diseases resulting from impairments of mitochondria. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Bockler A.,Radboud University Nijmegen | Bockler A.,Max Planck Institute for Human Cognitive and Brain Sciences | van der Wel R.P.R.D.,Rutgers University | Welsh T.N.,University of Toronto
Psychological Science | Year: 2014

Direct eye contact and motion onset are two powerful cues that capture attention. In the present study, we combined direct gaze with the sudden onset of motion to determine whether these cues have independent or shared influences. Participants identified targets presented randomly on one of four faces. Initially, two faces depicted direct gaze, and two faces depicted averted gaze. Simultaneously with or 900 ms before target presentation, one face with averted gaze switched to direct gaze, and one face with direct gaze switched to averted gaze. When gaze transitions and target presentation were simultaneous, the greatest response-time facilitation occurred at the location of the sudden onset of direct gaze. When target presentation was delayed, direct-gaze cues maintained a facilitatory influence, whereas motion cues induced an inhibitory influence. These findings reveal that gaze cues and motion cues at the same location influence information processing via independent and concurrently acting social and nonsocial attention channels. © The Author(s) 2014.

Ronacher K.,University of Cape Town | Joosten S.A.,Leiden University | van Crevel R.,Radboud University Nijmegen | Dockrell H.M.,London School of Hygiene and Tropical Medicine | And 2 more authors.
Immunological Reviews | Year: 2015

The spread of human immunodeficiency virus (HIV) infection within Africa led to marked increases in numbers of cases of tuberculosis (TB), and although the epidemic peaked in 2006, there were still 1.8 million new cases in 2013, with 29.2 million prevalent cases. Half of all TB cases in Africa are in those with HIV co-infection. A brief review of the well-documented main immunological mechanisms of HIV-associated increased susceptibility to TB is presented. However, a new threat is facing TB control, which presents itself in the form of a rapid increase in the number of people living with type II diabetes mellitus (T2DM), particularly in areas that are already hardest hit by the TB epidemic. T2DM increases susceptibility to TB threefold, and the TB burden attributable to T2DM is 15%. This review addresses the much smaller body of research information available on T2DM-TB, compared to HIV-TB comorbidity. We discuss the altered clinical presentation of TB in the context of T2DM comorbidity, changes in innate and adaptive immune responses, including lymphocyte subsets and T-cell phenotypes, the effect of treatment of the different comorbidities, changes in biomarker expression and genetic predisposition to the respective morbidities, and other factors affecting the comorbidity. Although significant gains have been made in improving our understanding of the underlying mechanisms of T2DM-associated increased susceptibility, knowledge gaps still exist that require urgent attention. © 2015 John Wiley & Sons A/S.

Demmel M.,University of Mainz | Saueressig F.,Radboud University Nijmegen | Zanusso O.,Friedrich - Schiller University of Jena
Annals of Physics | Year: 2015

We construct a novel Wetterich-type functional renormalization group equation for gravity which encodes the gravitational degrees of freedom in terms of gauge-invariant fluctuation fields. Applying a linear-geometric approximation the structure of the new flow equation is considerably simpler than the standard Quantum Einstein Gravity construction since only transverse-traceless and trace part of the metric fluctuations propagate in loops. The geometric flow reproduces the phase-diagram of the Einstein-Hilbert truncation including the non-Gaussian fixed point essential for Asymptotic Safety. Extending the analysis to the polynomial f(R)-approximation establishes that this fixed point comes with similar properties as the one found in metric Quantum Einstein Gravity; in particular it possesses three UV-relevant directions and is stable with respect to deformations of the regulator functions by endomorphisms. © 2015 Elsevier Inc.

Codello A.,International School for Advanced Studies | D'Odorico G.,Radboud University Nijmegen | Pagani C.,International School for Advanced Studies | Pagani C.,National Institute of Nuclear Physics, Italy
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2014

We construct a consistent closure for the beta functions of the cosmological and Newton's constants by evaluating the influence that the anomalous dimensions of the fluctuating metric and ghost fields have on their renormalization group flow. In this generalized framework we confirm the presence of a UV attractive non-Gaussian fixed point, which we find characterized by real critical exponents. Our closure method is general and can be applied systematically to more general truncations of the gravitational effective average action. © 2014 American Physical Society.

Heylen K.,Ghent University | Keltjens J.,Radboud University Nijmegen
Frontiers in Microbiology | Year: 2012

The genomes of two phenotypically denitrifying type strains of the genus Bacillus were sequenced and the pathways for dissimilatory nitrate reduction were reconstructed. Results suggest that denitrification proceeds in the periplasmic space and in an analogous fashion as in Gram-negative organisms, yet with the participation of proteins that tend to be membrane-bound or membrane-associated. A considerable degree of functional redundancy was observed with marked differences between B. azotoformans LMG 9581T and B. bataviensis LMG 21833T. In addition to the already characterized menaquinol/cyt c-dependent nitric oxide reductase (Suharti et al., 2001, 2004) of which the encoding genes could be identified now, evidence for another novel nitric oxide reductase (NOR) was found. Also, our analyses confirm earlier findings on branched electron transfer with both menaquinol and cytochrome c as reductants. Quite unexpectedly, both bacilli have the disposal of two parallel pathways for nitrite reduction enabling a life style as a denitrifier and as an ammonifying bacterium. © 2012 Heylen and Keltjens.

Hannink G.,Radboud University Nijmegen | Arts J.J.C.,Maastricht University
Injury | Year: 2011

Bone repair is a multi-dimensional process that requires osteogenic cells, an osteoconductive matrix, osteoinductive signalling, mechanical stability and vascularization. In clinical practice, bone substitute materials are being used for reconstructive purposes, bone stock augmentation, and bone repair. Over the last decade, the use of calcium phosphate (CaP) based bone substitute materials has increased exponentially. These bone substitute materials vary in composition, mechanical strength and biological mechanism of function, each having their own advantages and disadvantages. It is known that intrinsic material properties of CaP bone substitutes have a profound effect on their mechanical and biological behaviour and associated biodegradation. These material properties of bone substitutes, such as porosity, composition and geometry change the trade-off between mechanical and biological performance. The choice of the optimal bone substitutes is therefore not always an easy one, and largely depends on the clinical application and its associated biological and mechanical needs. Not all bone graft substitutes will perform the same way, and their performance in one clinical site may not necessarily predict their performance in another site. CaP bone substitutes unfortunately have yet to achieve optimal mechanical and biological performance and to date each material has its own trade-off between mechanical and biological performance. This review describes the effect of intrinsic material properties on biological performance, mechanical strength and biodegradability of CaP bone substitutes. © 2011 Elsevier Ltd. All rights reserved.

Verberk W.J.,Microlife Corporation | Kessels A.G.H.,Maastricht University | Thien T.,Radboud University Nijmegen
American Journal of Hypertension | Year: 2011

Background Screening for inter-arm difference (IAD) of blood pressure (BP) at each first visit is recommended by numerous guidelines whereas it is unclear whether the method by which IAD is measured has significant influence on the IAD value. Methods A systematic review is made of the studies reporting on double-arm measurements and the association of IAD with procedure characteristics (Medline/PubMed, Embase, and Cochrane Library). Results The mean absolute IAD was 5.4 ± 1.7 and 3.6 ± 1.2mmHg for systolic and diastolic BP, respectively. Of all subjects 14% had a systolic IAD ≥ 10mmHg, 4% a systolic IAD ≥ 20mmHg, and 7% a diastolic IAD ≥ 10mmHg. The relative risk (RR) of obtaining a systolic IAD 10 and ≥ 20mmHg and a diastolic IAD ≥ 10mmHg is higher when measuring sequentially instead of simultaneously (2.2 (95% CI: 1.4-3.6), P < 0.01; 4.8 (95% CI: 1.1-21.9), P < 0.05 and 2.5 (95% CI: 1.0-6.3) P < 0.05, respectively), when using a manual instead of an automated device (2.1 (95% CI: 1.1-3.9), P < 0.05; 4.4 (95% CI: 1.8-10.8), P < 0.01 and 3.7 (95% CI: 1.6-8.6), P < 0.01, respectively) and when performing only one BP measurement instead of multiple (2.0 (95% CI: 1.1-3.8), P < 0.05; 4.3 (95% CI: 1.6-11.4), P < 0.01 and 4.4 (95% CI: 1.7-11.4), P < 0.01, respectively). Conclusions creening for IAD of BP is important but the measurement methodology has a major influence on IAD results. To prevent overestimation and observer bias IAD should be assessed simultaneously at both arms, with one or two automatic devices and multiple readings should be taken. © 2011 American Journal of Hypertension, Ltd.

Bousema T.,London School of Hygiene and Tropical Medicine | Okell L.,Radboud University Nijmegen | Felger I.,Imperial College London | Drakeley C.,Swiss Tropical Institute
Nature Reviews Microbiology | Year: 2014

Most Plasmodium falciparum infections that are detected in community surveys are characterized by low-density parasitaemia and the absence of clinical symptoms. Molecular diagnostics have shown that this asymptomatic parasitic reservoir is more widespread than previously thought, even in low-endemic areas. In this Opinion article, we describe the detectability of asymptomatic malaria infections and the relevance of submicroscopic infections for parasite transmission to mosquitoes and for community interventions that aim at reducing transmission. We argue that wider deployment of molecular diagnostic tools is needed to provide adequate insight into the epidemiology of malaria and infection dynamics to aid elimination efforts. © 2014 Macmillan Publishers Limited. All rights reserved.

Martens K.,Radboud University Nijmegen | Golub A.,Arizona State University | Robinson G.,Morgan State University
Transportation Research Part A: Policy and Practice | Year: 2012

Transportation improvements inevitably lead to an uneven distribution of user benefits, in space and by network type (private and public transport). This paper makes a moral argument for what would be a fair distribution of these benefits. The argument follows Walzer's " Spheres of Justice" approach to define the benefits of transportation, access, as a sphere deserving a separate, non-market driven, distribution. That distribution, we propose, is one where the maximum gap between the lowest and highest accessibility, both by mode and in space, should be limited, while attempting to maximize average access. We then review transportation planning practice for a priori distributional goals and find little explicit guidance in conventional and even justice-oriented transportation planning and analyses. We end with a discussion of the implications for practice. © 2012 Elsevier Ltd.

Van Montfoort A.P.A.,Maastricht University | Hanssen L.L.P.,Radboud University Nijmegen | De Sutter P.,Ghent University | Viville S.,Institut Universitaire de France | And 2 more authors.
Human Reproduction Update | Year: 2012

Background: The subject of epigenetic risk of assisted reproduction treatment (ART), initiated by reports on an increase of children with the Beckwith-Wiedemann imprinting disorder, is very topical. Hence, there is a growing literature, including mouse studies. Methods: In order to gain information on transgenerational epigenetic inheritance and epigenetic effects induced by ART, literature databases were searched for papers on this topic using relevant keywords. Results: At the level of genomic imprinting involving CpG methylation, ART-induced epigenetic defects are convincingly observed in mice, especially for placenta, and seem more frequent than in humans. Data generally provide a warning as to the use of ovulation induction and in vitro culture. In human sperm from compromised spermatogenesis, sequence-specific DNA hypomethylation is observed repeatedly. Transmittance of sperm and oocyte DNA methylation defects is possible but, as deduced from the limited data available, largely prevented by selection of gametes for ART and/or non-viability of the resulting embryos. Some evidence indicates that subfertility itself is a risk factor for imprinting diseases. As in mouse, physiological effects from ART are observed in humans.In the human, indications for a broader target for changes in CpG methylation than imprinted DNA sequences alone have been found. In the mouse, a broader range of CpG sequences has not yet been studied. Also, a multigeneration study of systematic ART on epigenetic parameters is lacking. Conclusions: The field of epigenetic inheritance within the lifespan of an individual and between generations (via mitosis and meiosis, respectively) is growing, driven by the expansion of chromatin research. ART can induce epigenetic variation that might be transmitted to the next generation. © The Author 2012. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.

Guinea F.,CSIC - Institute of Materials Science | Katsnelson M.I.,Radboud University Nijmegen | Geim A.K.,University of Manchester
Nature Physics | Year: 2010

Among many remarkable qualities of graphene, its electronic properties attract particular interest owing to the chiral character of the charge carriers, which leads to such unusual phenomena as metallic conductivity in the limit of no carriers and the half-integer quantum Hall effect observable even at room temperature. Because graphene is only one atom thick, it is also amenable to external influences, including mechanical deformation. The latter offers a tempting prospect of controlling graphenes properties by strain and, recently, several reports have examined graphene under uniaxial deformation. Although the strain can induce additional Raman features, no significant changes in graphenes band structure have been either observed or expected for realistic strains of up to ∼15% (refs9, 10, 11). Here we show that a designed strain aligned along three main crystallographic directions induces strong gauge fields that effectively act as a uniform magnetic field exceeding 10 T. For a finite doping, the quantizing field results in an insulating bulk and a pair of countercirculating edge states, similar to the case of a topological insulator. We suggest realistic ways of creating this quantum state and observing the pseudomagnetic quantum Hall effect. We also show that strained superlattices can be used to open significant energy gaps in graphenes electronic spectrum. © 2010 Macmillan Publishers Limited. All rights reserved.

Brown G.D.,Aberdeen Group | Denning D.W.,University of Manchester | Gow N.A.R.,Aberdeen Group | Levitz S.M.,University of Massachusetts Medical School | And 2 more authors.
Science Translational Medicine | Year: 2012

Although fungal infections contribute substantially to human morbidity and mortality, the impact of these diseases on human health is not widely appreciated. Moreover, despite the urgent need for efficient diagnostic tests and safe and effective new drugs and vaccines, research into the pathophysiology of human fungal infections lags behind that of diseases caused by other pathogens. In this Review, we highlight the importance of fungi as human pathogens and discuss the challenges we face in combating the devastating invasive infections caused by these microorganisms, in particular in immunocompromised individuals.

Sauerwein R.W.,Radboud University Nijmegen | Bijker E.M.,Radboud University Nijmegen | Richie T.L.,U.S. Army
Current Opinion in Immunology | Year: 2010

Although significant progress has been made in clinical development, a protective malaria vaccine remains elusive. Here we review some of the immune subversive mechanisms used by the Plasmodium malaria parasite and propose a potentially effective strategy to achieve complete protection that may serve as a blue print for clinical usage. The premise is to modulate the immune response with drugs that neutralize suppressive functions and potentiate protective responses. Chloroquine may be a first attractive candidate facilitating protective cellular immune responses by improving cross-presentation and reducing suppressive regulatory T cell responses. © 2010 Elsevier Ltd.

van de Veerdonk F.L.,Radboud University Nijmegen | Netea M.G.,Radboud University Nijmegen | Dinarello C.A.,Radboud University Nijmegen | Dinarello C.A.,University of Colorado at Denver | Joosten L.A.B.,Radboud University Nijmegen
Trends in Immunology | Year: 2011

Interleukin-1β (IL-1β) and IL-18 contribute to host defense against infection by augmenting antimicrobial properties of phagocytes and initiating Th1 and Th17 adaptive immune responses. Protein complexes called inflammasomes activate intracellular caspase-1 autocatalytically, which cleaves the inactive precursors of IL-1β and IL-18 into bioactive cytokines. In this review, we discuss the controversies regarding inflammasome activation and the role of the inflammasome during infection. We highlight alternative mechanisms for processing IL-1β and IL-18 during infection, which involve extracellular cleavage of the inactive cytokines by neutrophil-derived serine proteases or proteases released from cytotoxic T cells. © 2011 Elsevier Ltd.

Guinea F.,CSIC - Institute of Materials Science | Geim A.K.,University of Manchester | Katsnelson M.I.,Radboud University Nijmegen | Novoselov K.S.,University of Manchester
Physical Review B - Condensed Matter and Materials Physics | Year: 2010

We analyze the mechanical deformations that are required to create uniform pseudomagnetic fields in graphene. It is shown that, if a ribbon is bent in-plane into a circular arc, this can lead to fields exceeding 10 T, which is sufficient for the observation of pseudo-Landau quantization. The arc geometry is simpler than those suggested previously and, in our opinion, has much better chances to be realized experimentally soon. The effects of a scalar potential induced by dilatation in this geometry is shown to be negligible. © 2010 The American Physical Society.

Koopman W.J.H.,Radboud University Nijmegen | Distelmaier F.,Heinrich Heine University Düsseldorf | Smeitink J.A.M.,Radboud University Nijmegen | Willems P.H.G.M.,Radboud University Nijmegen
EMBO Journal | Year: 2013

Mitochondrial oxidative phosphorylation (OXPHOS) sustains organelle function and plays a central role in cellular energy metabolism. The OXPHOS system consists of 5 multisubunit complexes (CI-CV) that are built up of 92 different structural proteins encoded by the nuclear (nDNA) and mitochondrial DNA (mtDNA). Biogenesis of a functional OXPHOS system further requires the assistance of nDNA-encoded OXPHOS assembly factors, of which 35 are currently identified. In humans, mutations in both structural and assembly genes and in genes involved in mtDNA maintenance, replication, transcription, and translation induce 'primary' OXPHOS disorders that are associated with neurodegenerative diseases including Leigh syndrome (LS), which is probably the most classical OXPHOS disease during early childhood. Here, we present the current insights regarding function, biogenesis, regulation, and supramolecular architecture of the OXPHOS system, as well as its genetic origin. Next, we provide an inventory of OXPHOS structural and assembly genes which, when mutated, induce human neurodegenerative disorders. Finally, we discuss the consequences of mutations in OXPHOS structural and assembly genes at the single cell level and how this information has advanced our understanding of the role of OXPHOS dysfunction in neurodegeneration. © 2013 European Molecular Biology Organization.

Dinarello C.A.,University of Colorado at Denver | Dinarello C.A.,Radboud University Nijmegen
Molecular Medicine | Year: 2014

There is an expanding role for interleukin (IL)-1 in diseases from gout to cancer. More than any other cytokine family, the IL-1 family is closely linked to innate inflammatory and immune responses. This linkage is because the cytoplasmic segment of all members of the IL-1 family of receptors contains a domain, which is highly homologous to the cytoplasmic domains of all toll-like receptors (TLRs). This domain, termed “toll IL-1 receptor (TIR) domain,” signals as does the IL-1 receptors; therefore, inflammation due to the TLR and the IL-1 families is nearly the same. Fundamental responses such as the induction of cyclo-oxygenase type 2, increased surface expression of cellular adhesion molecules and increased gene expression of a broad number of inflammatory molecules characterizes IL-1 signal transduction as it does for TLR agonists. IL-1β is the most studied member of the IL-1 family because of its role in mediating autoinflammatory disease. However, a role for IL-1α in disease is being validated because of the availability of a neutralizing monoclonal antibody to human IL-1α. There are presently three approved therapies for blocking IL-1 activity. Anakinra is a recombinant form of the naturally occurring IL-1 receptor antagonist, which binds to the IL-1 receptor and prevents the binding of IL-1β as well as IL-1α. Rilonacept is a soluble decoy receptor that neutralizes primarily IL-1β but also IL-1α. Canakinumab is a human monoclonal antibody that neutralizes only IL-1β. Thus, a causal or significant contributing role can be established for IL-1β and IL-1α in human disease. © 2014 Molecular Medicine All rights received.

Rovelli C.,Aix - Marseille University | Rovelli C.,University of Toulon | Vidotto F.,Radboud University Nijmegen
Physical Review Letters | Year: 2013

A simple argument indicates that covariant loop gravity (spin foam theory) predicts a maximal acceleration and hence forbids the development of curvature singularities. This supports the results obtained for cosmology and black holes using canonical methods. © 2013 American Physical Society.

Ulybyshev M.V.,Moscow State University | Buividovich P.V.,University of Regensburg | Katsnelson M.I.,Radboud University Nijmegen | Polikarpov M.I.,Moscow Institute of Physics and Technology
Physical Review Letters | Year: 2013

We report on the results of the first-principles numerical study of spontaneous breaking of chiral (sublattice) symmetry in suspended monolayer graphene due to electrostatic interaction, which takes into account the screening of Coulomb potential by electrons on σ orbitals. In contrast to the results of previous numerical simulations with unscreened potential, we find that suspended graphene is in the conducting phase with unbroken chiral symmetry. This finding is in agreement with recent experimental results by the Manchester group [D. C. Elias et al., Nat. Phys. 7, 701 (2011); A. S. Mayorov et al., Nano Lett. 12, 4629 (2012)]. Further, by artificially increasing the interaction strength, we demonstrate that suspended graphene is quite close to the phase transition associated with spontaneous chiral symmetry breaking, which suggests that fluctuations of chirality and nonperturbative effects might still be quite important. © 2013 American Physical Society.

Kirkpatrick J.P.,Duke University | van der Kogel A.J.,Radboud University Nijmegen | Schultheiss T.E.,City of Hope Cancer Center
International Journal of Radiation Oncology Biology Physics | Year: 2010

Dose-volume data for myelopathy in humans treated with radiotherapy (RT) to the spine is reviewed, along with pertinent preclinical data. Using conventional fractionation of 1.8-2 Gy/fraction to the full-thickness cord, the estimated risk of myelopathy is <1% and <10% at 54 Gy and 61 Gy, respectively, with a calculated strong dependence on dose/fraction (α/β = 0.87 Gy.) Reirradiation data in animals and humans suggest partial repair of RT-induced subclinical damage becoming evident about 6 months post-RT and increasing over the next 2 years. Reports of myelopathy from stereotactic radiosurgery to spinal lesions appear rare (<1%) when the maximum spinal cord dose is limited to the equivalent of 13 Gy in a single fraction or 20 Gy in three fractions. However, long-term data are insufficient to calculate a dose-volume relationship for myelopathy when the partial cord is treated with a hypofractionated regimen. © 2010 Elsevier Inc. All rights reserved.

de Pauw B.E.,Radboud University Nijmegen | Viscoli C.,University of Genoa
Journal of Antimicrobial Chemotherapy | Year: 2011

The management of invasive fungal disease in the immunocompromised host is complex and requires the specialized knowledge of physicians whose primary interest is actually the underlying disease rather than infectious complications. This Supplement aims to provide these physicians with some tools that may help to guide them through the maze of suspicion that an invasive fungal disease is present by offering an integrated care pathway of rational patient management. Such pathways will inevitably vary in detail in different centres and depend for their success on the presence of multidisciplinary teams and an explicit agreement on at least the minimum requirements for effective management. The integrated care pathways presented constitute an objective instrument to allow regular audits for recognizing opportunities to change practice if and when weaknesses are identified. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Doni G.,University of Applied Sciences and Arts Southern Switzerland | Doni G.,University of Lugano | Kostiainen M.A.,Radboud University Nijmegen | Danani A.,University of Applied Sciences and Arts Southern Switzerland | Pavan G.M.,University of Applied Sciences and Arts Southern Switzerland
Nano Letters | Year: 2011

In this work molecular dynamics simulation identifies a clear link between the dendron-virus multivalent molecular recognition and the nature of the consequent self-assembly. Data demonstrate how a weak hydrophobic association is transformed in an electrostatic self-assembly, orders of magnitude stronger, depending on the dendron generation used to assemble the viruses. This opens a new frontier in the engineering of hierarchical self-assemblies, potentially enabling the control of the supramolecular properties by acting at the single-molecule level. © 2010 American Chemical Society.

Eisinga R.,Radboud University Nijmegen | Breitling R.,University of Manchester | Heskes T.,Radboud University Nijmegen
FEBS Letters | Year: 2013

The rank product method is a widely accepted technique for detecting differentially regulated genes in replicated microarray experiments. To approximate the sampling distribution of the rank product statistic, the original publication proposed a permutation approach, whereas recently an alternative approximation based on the continuous gamma distribution was suggested. However, both approximations are imperfect for estimating small tail probabilities. In this paper we relate the rank product statistic to number theory and provide a derivation of its exact probability distribution and the true tail probabilities. © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Joosten L.A.B.,Radboud University Nijmegen | Netea M.G.,Radboud University Nijmegen | Dinarello C.A.,Radboud University Nijmegen | Dinarello C.A.,University of Colorado at Denver
Seminars in Immunology | Year: 2013

Although IL-1β is the master inflammatory cytokine in the IL-1 family, after more than ten years of continuous breeding, mice deficient in IL-1β exhibit no spontaneous disease. Therefore, one concludes that IL-1β is not needed for homeostasis. However, IL-1β-deficient mice are protected against local and systemic inflammation due to live infections, autoimmune processes, tumor metastasis and even chemical carcinogenesis. Based on a large number of preclinical studies, blocking IL-1β activity in humans with a broad spectrum of inflammatory conditions has reduced disease severity and for many, has lifted the burden of disease. Rare and common diseases are controlled by blocking IL-1β. Immunologically, IL-1β is a natural adjuvant for responses to antigen. Alone, IL-1β is not a growth factor for lymphocytes; rather in antigen activated immunocompetent cells, blocking IL-1 reduces IL-17 production. IL-1β markedly increases in the expansion of naive and memory CD4T cells in response to challenge with their cognate antigen. The response occurs when only specific CD4T cells respond to IL-1β and not to IL-6 or CD-28. A role for autophagy in production of IL-1β has emerged with deletion of the autophagy gene ATG16L1. Macrophages from ATG16L1-deficient mice produce higher levels of IL-1β after stimulation with TLR4 ligands via a mechanism of caspase-1 activation. The implications for increased IL-1β release in persons with defective autophagy may have clinical importance for disease. © 2013.

Riemenschneider M.J.,Heinrich Heine University Düsseldorf | Jeuken J.W.M.,Radboud University Nijmegen | Wesseling P.,Radboud University Nijmegen | Reifenberger G.,Heinrich Heine University Düsseldorf
Acta Neuropathologica | Year: 2010

Modern neuropathology serves a key function in the multidisciplinary management of brain tumor patients. Owing to the recent advancements in molecular neurooncology, the neuropathological assessment of brain tumors is no longer restricted to provide information on a tumor's histological type and malignancy grade, but may be complemented by a growing number of molecular tests for clinically relevant tissue-based biomarkers. This article provides an overview and critical appraisal of the types of genetic and epigenetic aberrations that have gained significance in the molecular diagnostics of gliomas, namely deletions of chromosome arms 1p and 19q, promoter hypermethylation of the O6-methylguanine-methyl-transferase (MGMT) gene, and the mutation status of the IDH1 and IDH2 genes. In addition, the frequent oncogenic aberration of BRAF in pilocytic astrocytomas may serve as a novel diagnostic marker and therapeutic target. Finally, this review will summarize recent mechanistic insights into the molecular alterations underlying treatment resistance in malignant gliomas and outline the potential of genome-wide profiling approaches for increasing our repertoire of clinically useful glioma markers. © 2010 The Author(s).

Dinarello C.A.,University of Colorado at Denver | Dinarello C.A.,Radboud University Nijmegen
European Journal of Immunology | Year: 2010

Although there has been a great amount of progress in the 25 years since the first reporting of the cDNA for IL-1α and IL-1β, the history of IL-1 goes back to the early 1940s. In fact, the entire field of inflammatory cytokines, TLR and the innate immune response can be found in the story of IL-1. This Viewpoint follows the steps from the identification of the fever-inducing activities of "soluble factors" produced by endotoxin-stimulated leukocytes through to the discovery of cryopyrin and the caspase-1 inflammasome and on to the clinical benefits of anti-IL-1β-based therapeutics. It also discusses some of the current controversies regarding the activation of the inflammasome. The future of novel anti-inflammatory agents to combat chronic inflammation is based, in part, on the diseases that are uniquely responsive to anti-IL-1β, which is surely a reason to celebrate the 25th anniversary of the cloning of IL-1α and IL-1β. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

Drose S.,University Hospital Frankfurt | Brandt U.,Radboud University Nijmegen | Brandt U.,Goethe University Frankfurt | Wittig I.,Goethe University Frankfurt
Biochimica et Biophysica Acta - Proteins and Proteomics | Year: 2014

The respiratory chain of the inner mitochondrial membrane is a unique assembly of protein complexes that transfers the electrons of reducing equivalents extracted from foodstuff to molecular oxygen to generate a proton-motive force as the primary energy source for cellular ATP-synthesis. Recent evidence indicates that redox reactions are also involved in regulating mitochondrial function via redox-modification of specific cysteine-thiol groups in subunits of respiratory chain complexes. Vice versa the generation of reactive oxygen species (ROS) by respiratory chain complexes may have an impact on the mitochondrial redox balance through reversible and irreversible thiol-modification of specific target proteins involved in redox signaling, but also pathophysiological processes. Recent evidence indicates that thiol-based redox regulation of the respiratory chain activity and especially S-nitrosylation of complex I could be a strategy to prevent elevated ROS production, oxidative damage and tissue necrosis during ischemia-reperfusion injury. This review focuses on the thiol-based redox processes involving the respiratory chain as a source as well as a target, including a general overview on mitochondria as highly compartmentalized redox organelles and on methods to investigate the redox state of mitochondrial proteins. This article is part of a Special Issue entitled: Thiol-Based Redox Processes. © 2014 Elsevier B.V.

Wehling T.O.,University of Hamburg | Yuan S.,Radboud University Nijmegen | Lichtenstein A.I.,University of Hamburg | Geim A.K.,University of Manchester | Katsnelson M.I.,Radboud University Nijmegen
Physical Review Letters | Year: 2010

We develop a first-principles theory of resonant impurities in graphene and show that a broad range of typical realistic impurities leads to the characteristic sublinear dependence of the conductivity on the carrier concentration. By means of density functional calculations various organic groups as well as adatoms such as H absorbed to graphene are shown to create midgap states within ±0.03eV around the neutrality point. A low energy tight-binding description is mapped out. Boltzmann transport theory as well as a numerically exact Kubo formula approach yield the conductivity of graphene contaminated with these realistic impurities in accordance with recent experiments. © 2010 The American Physical Society.

Netea M.G.,Radboud University Nijmegen | Van De Veerdonk F.L.,Radboud University Nijmegen | Van Der Meer J.W.M.,Radboud University Nijmegen | Dinarello C.A.,Radboud University Nijmegen | And 2 more authors.
Annual Review of Immunology | Year: 2015

Induction, production, and release of proinflammatory cytokines are essential steps to establish an effective host defense. Cytokines of the interleukin-1 (IL-1) family induce inflammation and regulate T lymphocyte responses while also displaying homeostatic and metabolic activities. With the exception of the IL-1 receptor antagonist, all IL-1 family cytokines lack a signal peptide and require proteolytic processing into an active molecule. One such unique protease is caspase-1, which is activated by protein platforms called the inflammasomes. However, increasing evidence suggests that inflammasomes and caspase-1 are not the only mechanism for processing IL-1 cytokines. IL-1 cytokines are often released as precursors and require extracellular processing for activity. Here we review the inflammasome-independent enzymatic processes that are able to activate IL-1 cytokines, paying special attention to neutrophil-derived serine proteases, which subsequently induce inflammation and modulate host defense. The inflammasome-independent processing of IL-1 cytokines has important consequences for understanding inflammatory diseases, and it impacts the design of IL-1-based modulatory therapies. © 2015 by Annual Reviews. All rights reserved.

Rogers T.R.,St James's Hospital | Slavin M.A.,Peter MacCallum Cancer Center | Donnelly J.P.,Radboud University Nijmegen
British Journal of Haematology | Year: 2011

Antifungal prophylaxis during treatment for haematological malignancies has been studied for 50years, yet it has not been wholly effective even when using antifungal drugs that exhibit potent activity in vitro against a broad range of fungal pathogens. Trials have demonstrated that it can reduce the incidence of invasive fungal diseases (IFD) and fungal deaths, but only two studies have had an impact on overall mortality. Furthermore, it has not significantly reduced the need for empirical antifungal therapy. Posaconazole was effective in preventing invasive aspergillosis in two studies of high-risk patients, and consensus guidelines grade it as a suitable choice for antifungal prophylaxis of invasive mould disease; however, its bioavailability was compromised by vomiting or diarrhoea so that an alternative parenteral antifungal drug was required. A recent trial of voriconazole prophylaxis after allogeneic stem cell transplantation failed to show superiority over fluconazole. With more accurate definitions of IFD, that utilize fungal biomarkers, such as galactomannan, together with computerized tomographic imaging, there is growing interest in a diagnostic-driven strategy, which could prove to be a more efficacious approach. © 2011 Blackwell Publishing Ltd.

Dinarello C.A.,University of Colorado at Denver | Dinarello C.A.,Radboud University Nijmegen | van der Meer J.W.M.,Radboud University Nijmegen
Seminars in Immunology | Year: 2013

IL-1 is a master cytokine of local and systemic inflammation. With the availability of specific IL-1 targeting therapies, a broadening list of diseases has revealed the pathologic role of IL-1-mediated inflammation. Although IL-1, either IL-1α or IL-1β, was administered to patients in order to improve bone marrow function or increase host immune responses to cancer, these patients experienced unacceptable toxicity with fever, anorexia, myalgias, arthralgias, fatigue, gastrointestinal upset and sleep disturbances; frank hypotension occurred. Thus it was not unexpected that specific pharmacological blockade of IL-1 activity in inflammatory diseases would be beneficial. Monotherapy blocking IL-1 activity in a broad spectrum of inflammatory syndromes results in a rapid and sustained reduction in disease severity. In common conditions such as heart failure and gout arthritis, IL-1 blockade can be effective therapy. Three IL-1blockers have been approved: the IL-1 receptor antagonist, anakinra, blocks the IL-1 receptor and therefore reduces the activity of IL-1α and IL-1β. A soluble decoy receptor, rilonacept, and a neutralizing monoclonal anti-interleukin-1β antibody, canakinumab, are also approved. A monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1α are in clinical trials. By specifically blocking IL-1, we have learned a great deal about the role of this cytokine in inflammation but equally important, reducing IL-1 activity has lifted the burden of disease for many patients. © 2013.

Vermeulen E.,Catholic University of Leuven | Lagrou K.,Catholic University of Leuven | Lagrou K.,University Hospitals Leuven | Verweij P.E.,Radboud University Nijmegen
Current Opinion in Infectious Diseases | Year: 2013

PURPOSE OF REVIEW: Reports from the end of the 2000s forced the medical community to take azole resistance in Aspergillus fumigatus into account. Not only patients with chronic aspergillus disease, who develop resistance during long-term azole treatment, but also azole-naive patients are at risk, owing to the presence of resistant strains in the environment. The purpose of this review is to overview the latest findings concerning the origin, evolution, and implications of azole resistance in A. fumigatus. RECENT FINDINGS: TR34/L98H is the predominant resistance mechanism of environmental origin in A. fumigatus. Recent epidemiological data show that this mechanism is an expanding problem, with reports from China, Iran, and India. However, the TR34/L98H strains from the Middle East are genotypically different from the European isolates; their emergence is, therefore, not due to simple geographical spread of the 'European' isolates. A new environmental resistance mechanism, TR46/Y121F/T289A, was detected in the Netherlands, conferring voriconazole resistance. In patients chronically treated with triazoles, the spectrum of resistance has become more diverse, with the emergence of non-CYP51A-mediated mechanisms. Central registration of treatment and outcome data of patients with resistant aspergillus disease are needed. SUMMARY: Azole resistance in A. fumigatus is evolving to a global health problem. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Cutolo M.,University of Genoa | Kitas G.D.,Dudley Group NHS Foundation Trust | Kitas G.D.,University of Manchester | van Riel P.L.C.M.,Radboud University Nijmegen
Seminars in Arthritis and Rheumatism | Year: 2014

Objective: The disease burden in rheumatoid arthritis (RA) extends beyond the joint. This article evaluates the physical and psychosocial extra-articular burden of treated RA and relationships among diverse disease manifestations. Methods: MEDLINE searches identified papers published in English from January 2003 to December 2012 that evaluated systemic complications and psychosocial aspects associated with RA. Preference was given to studies with randomized cohorts and large (>100) sample sizes. Of 378 articles identified in the initial search, 118 were selected for inclusion. Results: RA is associated with multiple comorbidities and psychosocial impairments, including cardiovascular disease, osteoporosis, interstitial lung disease, infection, malignancies, fatigue, depression, cognitive dysfunction, reduced work performance, work disability, and decreased health-related quality of life. The etiology of the extra-articular burden may reflect the systemic inflammation and immune system alteration associated with RA, metabolic imbalances and side effects related to treatment, or the influence of comorbidities. Strategies that may help to reduce the extra-articular disease burden include personalized medicine and the potential introduction of treatments with new mechanisms of action. Conclusion: Despite improvements in treating joint disease, the extra-articular burden in RA remains substantial, encompassing multiple comorbidities and psychosocial impairments. © 2014 Elsevier Inc.

Todorov A.,Princeton University | Olivola C.Y.,Carnegie Mellon University | Dotsch R.,Radboud University Nijmegen | Mende-Siedlecki P.,Princeton University
Annual Review of Psychology | Year: 2015

Since the early twentieth century, psychologists have known that there is consensus in attributing social and personality characteristics from facial appearance. Recent studies have shown that surprisingly little time and effort are needed to arrive at this consensus. Here we review recent research on social attributions from faces. Section I outlines data-driven methods capable of identifying the perceptual basis of consensus in social attributions from faces (e.g., What makes a face look threatening?). Section II describes nonperceptual determinants of social attributions (e.g., person knowledge and incidental associations). Section III discusses evidence that attributions from faces predict important social outcomes in diverse domains (e.g., investment decisions and leader selection). In Section IV, we argue that the diagnostic validity of these attributions has been greatly overstated in the literature. In the final section, we offer an account of the functional significance of these attributions. © 2015 by Annual Reviews. All rights reserved.

Bittencourt L.K.,Federal University of Rio de Janeiro | Barentsz J.O.,Radboud University Nijmegen | De Miranda L.C.D.,Federal University of Rio de Janeiro | Gasparetto E.L.,Federal University of Rio de Janeiro
European Radiology | Year: 2012

Objectives: To investigate the usefulness of Apparent Diffusion Coefficients (ADC) in predicting prostatectomy Gleason Grades (pGG) and Scores (GS), compared with ultrasound-guided biopsy Gleason Grades (bGG). Methods: Twenty-four patients with biopsy-proven prostate cancer were included in the study. Diffusion-weighted images were obtained using 1.5-T MR with a pelvic phased-array coil. Median ADC values (b0,500,1000 s/mm2) were measured at the most suspicious areas in the peripheral zone. The relationship between ADC values and pGG or GS was assessed using Pearson's coefficient. The relationship between bGG and pGG or GS was also evaluated. Receiver operating characteristic (ROC) curve analysis was performed to assess the performance of each method on a qualitative level. Results: A significant negative correlation was found between mean ADCs of suspicious lesions and their pGG (r = -0.55; p < 0.01) and GS (r = -0.63; p < 0.01). No significant correlation was found between bGG and pGG (r = 0.042; p > 0.05) or GS (r = 0.048; p > 0.05). ROC analysis revealed a discriminatory performance of AUC = 0.82 for ADC and AUC = 0.46 for bGG in discerning low-grade from intermediate/high-grade lesions. Conclusions: The ADC values of suspicious areas in the peripheral zone perform better than bGG in the correlation with prostate cancer aggressiveness, although with considerable intra-subject heterogeneity. Key Points: • Prostate cancer aggressiveness is probably underestimated and undersampled by routine ultrasound-guided biopsies. • Diffusion-weighted MR images show good linear correlation with prostate cancer aggressiveness. • DWI information may be used to improve risk-assessment in prostate cancer. © 2011 European Society of Radiology.

Mende-Siedlecki P.,Princeton University | Cai Y.,Princeton University | Todorov A.,Princeton University | Todorov A.,Radboud University Nijmegen
Social Cognitive and Affective Neuroscience | Year: 2013

Person perception is a dynamic, evolving process. Because other people are an endless source of social information, people need to update their impressions of others based upon new information. We devised an fMRI study to identify brain regions involved in updating impressions. Participants saw faces paired with valenced behavioral information and were asked to form impressions of these individuals. Each face was seen five times in a row, each time with a different behavioral description. Critically, for half of the faces the behaviors were evaluatively consistent, while for the other half they were inconsistent. In line with prior work, dorsomedial prefrontal cortex (dmPFC) was associated with forming impressions of individuals based on behavioral information. More importantly, a whole-brain analysis revealed a network of other regions associated with updating impressions of individuals who exhibited evaluatively inconsistent behaviors, including rostrolateral PFC, superior temporal sulcus, right inferior parietal lobule and posterior cingulate cortex. © The Author (2012). Published by Oxford University Press.

De Weerth C.,Radboud University Nijmegen | Fuentes S.,Radboud University Nijmegen | Puylaert P.,Radboud University Nijmegen | Puylaert P.,Wageningen University | De Vos W.M.,University of Helsinki
Pediatrics | Year: 2013

OBJECTIVES: To provide a comprehensive analysis of the fecal microbiota in infants with colic, as compared with control infants, during their first 100 days of life. METHODS: Microbial DNA of .200 samples from 12 infants with colic and 12 age-matched control infants was extracted and hybridized to a phylogenetic microarray. RESULTS: Microbiota diversity gradually increased after birth only in the control group; moreover, in the first weeks, the diversity of the colic group was significantly lower than that of the control group. The stability of the successive samples also appeared to be significantly lower in the infants with colic for the first weeks. Further analyses revealed which bacterial groups were responsible for colic-related differences in microbiota at age 1 or 2 weeks, the earliest ages with significant differences. Proteobacteria were significantly increased in infants with colic compared with control infants, with a relative abundance that was more than twofold. In contrast, bifidobacteria and lactobacilli were significantly reduced in infants with colic. Moreover, the colic phenotype correlated positively with specific groups of proteobacteria, including bacteria related to Escherichia, Klebsiella, Serratia, Vibrio, Yersinia, and Pseudomonas, but negatively with bacteria belonging to the Bacteroidetes and Firmicutes phyla, the latter of which includes some lactobacilli and canonical groups known to produce butyrate and lactate. CONCLUSIONS: The results indicate the presence of microbial signatures in the first weeks of life in infants who later develop colic. These microbial signatures may be used to understand the excessive crying. The results offer opportunities for early diagnostics as well as for developing specific therapies. Copyright © 2013 by the American Academy of Pediatrics.

Groot P.J.,California Institute of Technology | Groot P.J.,Radboud University Nijmegen
Astrophysical Journal | Year: 2012

In eclipsing binaries the stellar rotation of the two components will cause a rotational Doppler beaming during eclipse ingress and egress when only part of the eclipsed component is covered. For eclipsing binaries with fast spinning components this photometric analog of the well-known spectroscopic Rossiter-McLaughlin effect can exceed the strength of the orbital effect. Example light curves are shown for a detached double white dwarf binary, a massive O-star binary and a transiting exoplanet case, similar to WASP-33b. Inclusion of the rotational Doppler beaming in eclipsing systems is a prerequisite for deriving the correct stellar parameters from fitting high-quality photometric light curves and can be used to determine stellar obliquities as well as, e.g., an independent measure of the rotational velocity in those systems that may be expected to be fully synchronized. © 2012 The American Astronomical Society. All rights reserved.

Garcia-Palacios P.,Colorado State University | Maestre F.T.,Rey Juan Carlos University | Bardgett R.D.,Lancaster University | de Kroon H.,Radboud University Nijmegen
Journal of Ecology | Year: 2012

Recent evidence suggests that soil nutrient heterogeneity, a ubiquitous feature of terrestrial ecosystems, modulates plant responses to ongoing global change (GC). However, we know little about the overall trends of such responses, the GC drivers involved and the plant attributes affected. We synthesized literature to answer the question: Does soil heterogeneity significantly affect plant responses to main GC drivers, such as elevated atmospheric carbon dioxide concentration (CO 2), nitrogen (N) enrichment and changes in rainfall regime? Overall, most studies have addressed short-term effects of N enrichment on the performance of model plant communities using experiments conducted under controlled conditions. The role of soil heterogeneity as a modulator of plant responses to elevated CO 2 may depend on the plasticity in nutrient uptake patterns. Soil heterogeneity does interact with N enrichment to determine plant growth and nutrient status, but the outcome of this interaction has been found to be both synergistic and inhibitory. The very few studies published on interactive effects of soil heterogeneity and changes in rainfall regime prevented us from identifying any general pattern. We identify the long-term consequences of soil heterogeneity on plant community dynamics in the field, and the ecosystem-level responses of the soil heterogeneity × GC driver interaction, as the main knowledge gaps in this area of research. To fill these gaps and take soil heterogeneity and GC research a step forward, we propose the following research guidelines: (i) combining morphological and physiological plant responses to soil heterogeneity with field observations of community composition and predictions from simulation models and (ii) incorporating soil heterogeneity into a trait-based response-effect framework, where plant-resource-use traits are used as both response variables to this heterogeneity and GC, and predictors of ecosystem functioning. Synthesis. There is enough evidence to affirm that soil heterogeneity modulates plant responses to elevated atmospheric CO 2 and N enrichment. Our synthesis indicates that we must explicitly consider soil heterogeneity to accurately predict plant responses to GC drivers. © 2012 The Authors. Journal of Ecology © 2012 British Ecological Society.

Stenman L.K.,University of Helsinki | Holma R.,University of Helsinki | Eggert A.,Radboud University Nijmegen | Korpela R.,University of Helsinki
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2013

Impairment of gut barrier is associated with a fat-rich diet, but mechanisms are unknown. We have earlier shown that dietary fat modifies fecal bile acids in mice, decreasing the proportion of ursodeoxycholic acid (UDCA) vs. de-oxycholic acid (DCA). To clarify the potential role of bile acids in fat-induced barrier dysfunction, we here investigated how physiological concentrations of DCA and UDCA affect barrier function in mouse intestinal tissue. Bile acid experiments were conducted in vitro in Using chambers using 4- and 20-kDa FITC-labeled dextrans. Epithelial integrity and inflammation were assayed by histology and Western blot analysis for cyclooxygenase-2. LPS was studied in DCA-induced barrier dysfunction. Finally, we investigated in a 10-wk in vivo feeding trial in mice the barrier-disrupting effect of a diet containing 0.1% DCA. DCA disrupted epithelial integrity dose dependently at 1-3 mM, which correspond to physiological concentrations on a high-fat diet. Low-fat diet-related concentrations of DCA had no effect. In vivo, the DCA-containing diet increased intestinal permeability 1.5-fold compared with control (P = 0.016). Hematoxylin-eosin staining showed a clear disruption of the epithelial barrier by 3 mM DCA in vitro. A short-term treatment by DCA did not increase cyclooxygenase-2 content in colon preparations. UDCA did not affect barrier function itself, but it ameliorated DCA-induced barrier disruption at a 0.6 mM concentration. LPS had no significant effect on barrier function at 0.5-4.5 μg/ml concentrations. We suggest a novel mechanism for barrier dysfunction on a high-fat diet involving the effect of hydrophobic luminal bile acids. © 2013 the American Physiological Society.

Bahlmann J.,University of Lübeck | Bahlmann J.,University of California at Berkeley | Aarts E.,University of California at Berkeley | D'Esposito M.,University of California at Berkeley | D'Esposito M.,Radboud University Nijmegen
Journal of Neuroscience | Year: 2015

The frontal cortex mediates cognitive control and motivation to shape human behavior. It is generally observed that medial frontal areas are involved in motivational aspects of behavior, whereas lateral frontal regions are involved in cognitive control. Recent models of cognitive control suggest a rostro-caudal gradient in lateral frontal regions, such that progressively more rostral (anterior) regions process more complex aspects of cognitive control. How motivation influences such a control hierarchy is still under debate. Although some researchers argue that both systems work in parallel, others argue in favor of an interaction between motivation and cognitive control. In the latter case it is yet unclear how motivation would affect the different levels of the control hierarchy. This was investigated in the present functional MRI study applying different levels of cognitive control under different motivational states (low vs high reward anticipation). Three levels of cognitive control were tested by varying rule complexity: stimulus-response mapping (low-level), flexible task updating (mid-level), and sustained cue-task associations (high-level). We found an interaction between levels of cognitive control and motivation in medial and lateral frontal subregions. Specifically, flexible updating (mid-level of control) showed the strongest beneficial effect of reward and only this level exhibited functional coupling between dopamine-rich midbrain regions and the lateral frontal cortex. These findings suggest that motivation differentially affects the levels of a control hierarchy, influencing recruitment of frontal cortical control regions depending on specific task demands. © 2015 the authors.

Coppus A.M.W.,Center for the Intellectually Disabled | Coppus A.M.W.,Radboud University Nijmegen | Coppus A.M.W.,Erasmus Medical Center
Developmental Disabilities Research Reviews | Year: 2013

Increases in the life expectancy of people with Intellectual Disability have followed similar trends to those found in the general population. With the exception of people with severe and multiple disabilities or Down syndrome, the life expectancy of this group now closely approximates with that of the general population. Middle and old age, which until 30 years ago were not recognized in this population, are now important parts of the life course of these individuals. Older adults with Intellectual Disabilities form a small, but significant and growing proportion of older people in the community. How these persons grow older and how symptoms and complications of the underlying cause of the Intellectual Disability will influence their life expectancy is of the utmost importance. © 2013 Wiley Periodicals, Inc.

Sterry W.,Charité - Medical University of Berlin | Van De Kerkhof P.,Radboud University Nijmegen
Journal of the European Academy of Dermatology and Venereology | Year: 2012

Psoriasis is a chronic, genetically predisposed skin disorder, characterised by thickened scaly plaques. Although no therapy is recognised as curative, therapies aimed at symptom control include biologic agents that are generally designed to block molecular activation of cellular pathways of a pathogenic immune response. Although biologics are often described as a class, they can be further sub-classified according to properties including structure and molecular target. For example, the two main groups of biologics for the treatment of psoriasis are those targeting cytokines and those targeting T-cells or antigen-presenting cells. Agents that inhibit cytokines can be broadly split into anti-p40 agents, which target the p40 subunit of IL-12 and IL-23 (such as ustekinumab), and anti-TNF agents. Anti-TNF agents may then be further divided into soluble receptors (etanercept) and monoclonal antibodies (adalimumab and infliximab). Even within the same subclass, agents may display variations in structure, function, route of administration and pharmacokinetics, which are reflected in their clinical profiles. For example, of the TNF antagonists, infliximab, provides a rapid onset of response, high efficacy, high peak serum concentrations, anti-granulomatous activity, potential for tuberculosis reactivation and frequent antibody formation; adalimumab provides a fast response, high efficacy, potential for tuberculosis reactivation and the possibility of antibody formation; and etanercept provides a slower response, good efficacy, rare antibody formation and is rarely linked to tuberculosis cases. This suggests that biologic agents exhibit unique properties, which appear to be more relevant than a 'class effect' in assessing risk-benefit profiles for this diverse group of drugs. With a range of agents available, studying the immunogenesis of psoriasis is likely to be useful in profiling individuals best suited to the characteristics of particular drugs. It should also be noted that because differences between agents may affect safety profiles, long-term patient registries are an important tool to assess tolerability and develop guidelines for the most effective use of these drugs. © 2012 European Academy of Dermatology and Venereology.

Todorov A.,Princeton University | Todorov A.,Radboud University Nijmegen | Porter J.M.,Columbia University
Psychological Science | Year: 2014

Studies on first impressions from facial appearance have rapidly proliferated in the past decade. Almost all of these studies have relied on a single face image per target individual, and differences in impressions have been interpreted as originating in stable physiognomic differences between individuals. Here we show that images of the same individual can lead to different impressions, with within-individual image variance comparable to or exceeding between-individuals variance for a variety of social judgments (Experiment 1). We further show that preferences for images shift as a function of the context (e.g., selecting an image for online dating vs. a political campaign; Experiment 2), that preferences are predictably biased by the selection of the images (e.g., an image fitting a political campaign vs. a randomly selected image; Experiment 3), and that these biases are evident after extremely brief (40-ms) presentation of the images (Experiment 4). We discuss the implications of these findings for studies on the accuracy of first impressions. © The Author(s) 2014.

Rekvig O.P.,University of Tromsø | Van Der Vlag J.,Radboud University Nijmegen
Seminars in Immunopathology | Year: 2014

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with various clinical manifestations affecting different tissues. A characteristic feature of SLE is the presence of autoantibodies against double-stranded (ds)DNA, histones and nucleosomes, and other chromatin components. SLE is a prototype type III hypersensitivity reaction. Local deposition of anti-nuclear antibodies in complex with released chromatin induces serious inflammatory conditions by activation of the complement system. The severe renal manifestation, lupus nephritis, is classified based on histological findings in renal biopsies. Apoptotic debris, including chromatin, is present in the extracellular matrix and circulation of patients with SLE. This may be due to an aberrant process of apoptosis and/or insufficient clearance of apoptotic cells/chromatin. The non-cleared apoptotic debris may lead to activation of both the innate and adaptive immune systems. In addition, an aberrant presentation of peptides by antigen-presenting cells, disturbed selection processes for lymphocytes, and deregulated lymphocyte responses may be involved in the development of autoimmunity. In the present review, we briefly will summarize current knowledge on the pathogenesis of SLE. We will also critically discuss and challenge central issues that need to be addressed in order to fully understand the pathogenic mechanisms involved in the development of SLE and in order to have an improved diagnosis for SLE. Disappointingly, in our opinion, there are still more questions than answers for the pathogenesis, diagnosis, and treatment of SLE. © 2014 Springer-Verlag.

News Article | March 10, 2016

Clamming up could help underwater seagrass meadows better withstand drought, heat waves and climate change. Breakdown of a symbiotic bond between seagrasses off the West Africa coast and tiny lucinid clams can exacerbate damage in hard times, researchers say March 10 in Current Biology. So protecting meadows may mean worrying just as much about the partnership as the seagrasses themselves, says coauthor Tjisse van der Heide of Radboud University Nijmegen in the Netherlands. Seagrasses aren’t seaweed like kelp. They’re genuine flowering plants whose ancestors over about 100 million years adapted to a salty underwater life that would quickly kill most land plants (SN: 12/5/09, p. 22). Clams can play a role in easing one risk of this life: debris breakdown that goes toxic. Their own dead leaves plus floating bits of dead stuff and waste, including runoff from nearby land, snag in a seagrass meadow’s expanse of swaying leaves. Sea-bottom microbes that break down the rain of debris release sulfides, which can poison the plants. In 2012, van der Heide and colleagues proposed that in some seagrass communities, especially in the tropics and subtropics, clams burrowing among the plant roots help detoxify sulfides. The Loripes clams and other species in the lucinid group benefit from oxygen that plant roots give off, and the sulfides from debris breakdown nourish symbiotic bacteria in the clams. “They’re farming bacteria in their gills,” says van der Heide. As the bacteria feast, they leak sugars that nourish their clam, and the toxic sulfides are turned into harmless sulfates, lowering the toxic risks to seagrasses. Not every seagrass meadow has lucinid clams, but intertidal meadows at Banc d’Arguin in Mauritania do. The clam density there can average 1,500 to 2,000 small clams per square meter in the top 10 centimeters or so of mud. At low tides, mats of seagrasses lie exposed to air for hours at a time. During the severe drought of 2011, the hot, thirsty air desiccated swaths of the meadow. Dying plants faltered in oxygenating the clams and their bacteria, causing a cascade of effects that weakened the detoxification process. As drought-stricken seagrasses and clams failed to provide each other with benefits, a feedback loop of increasingly worse performance for both partners accelerated their demise, van der Heide and his colleagues propose. That’s the scenario they draw from satellite data on the meadow during the drought. Seeing considerable living patches mix with dead zones at the same elevation and exposed to the same climate conditions points to something else — such as a mutualism breakdown — speeding the change from leafy to bald. Comparing seagrass patches that died with patches that survived, van der Heide and his colleagues propose that maintaining the clam partnership made a difference. Of 32 plots of meadow, the half where seagrasses survived the drought had nine times as many clams as the dead zones. These survival spots also averaged only about a quarter of the toxic sulfides. This seagrass-clam mutualism may be important in Banc d’Arguin but has yet to be demonstrated as a more general phenomenon, says marine ecologist Carlos Duarte of King Abdullah University of Science and Technology in Thuwal, Saudi Arabia.

News Article | March 23, 2016

The event was catastrophic on a cosmic scale — a merger of black holes that violently shook the surrounding fabric of space and time, and sent a blast of space-time vibrations known as gravitational waves rippling across the Universe at the speed of light. But it was the kind of calamity that physicists on Earth had been waiting for. On 14 September, when those ripples swept across the freshly upgraded Laser Interferometer Gravitational-Wave Observatory (Advanced LIGO), they showed up as spikes in the readings from its two L-shaped detectors in Louisiana and Washington state. For the first time ever, scientists had recorded a gravitational-wave signal. “There it was!” says LIGO team member Daniel Holz, an astrophysicist at the University of Chicago in Illinois. “And it was so strong, and so beautiful, in both detectors.” Although the shape of the signal looked familiar from the theory, Holz says, “it's completely different when you see something in the data. It's this transcendent moment”. The signal, formally designated GW150914 after the date of its occurrence and informally known to its discoverers as 'the Event', has justly been hailed as a milestone in physics. It has provided a wealth of evidence for Albert Einstein's century-old general theory of relativity, which holds that mass and energy can warp space-time, and that gravity is the result of such warping. Stuart Shapiro, a specialist in computer simulations of relativity at the University of Illinois at Urbana–Champaign, calls it “the most significant confirmation of the general theory of relativity since its inception”. But the Event also marks the start of a long-promised era of gravitational-wave astronomy. Detailed analysis of the signal has already yielded insights into the nature of the black holes that merged, and how they formed. With more events such as these — the LIGO team is analysing several other candidate events captured during the detectors' four-month run, which ended in January — researchers will be able to classify and understand the origins of black holes, just as they are doing with stars. Still more events should appear starting in September, when Advanced LIGO is scheduled to begin joint observations with its European counterpart, the Franco–Italian-led Advanced Virgo facility near Pisa, Italy. (The two collaborations already pool data and publish papers together.) This detector will not only contribute crucial details to events, but could also help astronomers to make cosmological-distance measurements more accurately than before. “It's going to be a really good ride for the next few years,” says Bruce Allen, managing director of the Max Planck Institute for Gravitational Physics in Hanover, Germany. “The more black holes they see whacking into each other, the more fun it will be,” says Roger Penrose, a theoretical physicist and mathematician at the University of Oxford, UK, whose work in the 1960s helped to lay the foundation for the theory of the objects. “Suddenly, we have a new way of looking at the Universe.” Physicists have known for decades that every pair of orbiting bodies is a source of gravitational waves. With each revolution, according to Einstein's equations, the waves will carry away a tiny fraction of their orbital energy. This will cause the objects to move a bit closer together and orbit a little faster. For familiar pairs, such as the Moon and Earth, such energy loss is imperceptible even on timescales of billions of years. But dense objects in very close orbits can lose energy much more quickly. In 1974, radio astronomers Russell Hulse and Joseph Taylor, then of the University of Massachusetts Amherst, found just such a system: a pair of dense neutron stars in orbit around each other. As the years went by, the scientists found that this 'binary pulsar' was losing energy and spiralling inwards exactly as predicted by Einstein's theory. The two black holes detected by LIGO had probably been losing energy in this way for millions, if not billions, of years before they reached the end. But LIGO did not register the gravitational waves coming from them until 9:50:45 Coordinated Universal Time on 14 September, when the wave's frequency rose above some 30 cycles per second (hertz) — corresponding to 15 full black-hole orbits per second — and was finally high enough for the detectors to distinguish it from background noise. But then, in just 0.2 seconds, LIGO watched the signal surge to 250 hertz and suddenly disappear, as the black holes made their final 5 orbits, reached orbital velocities of half the speed of light and coalesced into a single massive object (see 'What made the wave'). The LIGO and Virgo teams soon went to work extracting every bit of information possible. At the most fundamental level, the signal gave them an existence proof: the fact that the objects came so close to each other before merging meant that they had to be black holes, because ordinary stars would need to be much bigger. “It is, I think, the clearest indication that black holes are really there,” says Penrose. The signal also provided researchers with the first empirical test of general relativity beyond regions — including the space around the binary pulsar — where there is comparatively little space-time warping. There was no empirical evidence that the theory would keep its validity at the extreme energies of merging black holes, says Shapiro — but it did. The signal held a trove of more-detailed information as well. By scrutinizing its shape just before the final cataclysm, the scientists found that it closely approximated a simple sine wave with a steadily increasing frequency and amplitude. According to B. S. Sathyaprakash, a theoretical physicist at Cardiff University, UK, and a senior LIGO researcher, this pattern suggests that the orbits of the black holes were nearly circular, and that LIGO probably had a bird's-eye view of the circles, looking almost straight down on them rather than edge-on. In addition, the LIGO and Virgo teams were able to use the frequency of the observed wave, along with its rate of acceleration, to estimate the masses of the two black holes: because heavier objects radiate energy in the form of gravitational waves at a faster rate than do lighter objects, their pitch rises more quickly. By recreating the Event with computer simulations, the scientists calculated that the two black holes weighed about 36 times and 29 times the mass of the Sun, respectively, and that the combined black hole weighed about 62 solar masses1. The lost difference, about three Suns' worth, was dispersed as gravitational radiation — much of it during what physicists call the 'ringdown' phase, when the merged black hole was settling into a spherical shape. (For comparison, the most powerful thermonuclear bomb ever detonated converted only about 2 kilograms of matter into energy — roughly 1030 times less.) The teams also suspect that the final black hole was spinning at perhaps 100 revolutions per second, although the margin of error on that estimate is large. The inferred masses of the two black holes are also revealing. Each object was presumably the remnant of a very massive star, with the larger star approaching 100 times the mass of the Sun and the smaller one a little less. Thermonuclear reactions are known to convert hydrogen in the cores of such stars into helium much faster than in lighter stars, which leads them to collapse under their own weight only a few million years after they are born. The energy released by this collapse causes an explosion called a type II supernova, which leaves behind a residual core that turns into a neutron star or, if it's massive enough, a black hole. Scientists say that type II supernovae should not produce black holes much bigger than about 30 solar masses — and both black holes were at the high end of that range. This could mean that the system formed from interstellar gas clouds that were richer in hydrogen and helium than the ones typically found in our Galaxy, and that were poorer in heavy elements — which astronomers call metals. Astrophysicists have calculated that stars formed from such low-metallicity clouds should have an easier time forming massive black holes when they explode, explains Gijs Nelemans, an astronomer at Radboud University Nijmegen in the Netherlands and a member of the Advanced Virgo collaboration. That's because during a supernova explosion, smaller atoms are less likely to be blown away by the blast. Low-metallicity stars thus “lose less mass, so more of it goes into the black hole, for the same initial mass”, Nelemans says. But how did these two black holes end up in a binary system? In a paper2 published at the same time as the one reporting the discovery, the LIGO and Virgo teams described two commonly accepted scenarios. The simplest one is that two massive stars were born as a binary-star system, forming from the same interstellar gas cloud like a double-yolked egg, and orbiting each other ever since. (Such binary stars are common in our Galaxy; singletons such as the Sun are the exception, rather than the rule.) After a few million years, one of the stars would have burned out and gone supernova, soon to be followed by the other. The result would be a binary black hole. The second scenario is that the stars formed independently, but still inside the same dense stellar cluster — perhaps one similar to the globular clusters that orbit the Milky Way. In such a cluster, massive stars would sink towards the centre and, through complex interactions with lighter stars, form binary systems, possibly long after their transformation into black holes. Simulations made by Simon Portegies Zwart, an astrophysicist at Leiden University in the Netherlands, show3 that massive stars are more likely to form in dense clusters, where collisions and mergers are more common. He also finds that once a binary black-hole system forms, the complex dynamics of the cluster's centre would probably kick the pair out at high speed. The binary that Advanced LIGO detected may have wandered away from any galaxy for billions of years before merging, he says. Although the LIGO and Virgo teams were able to learn a lot from the Event, there is much more that gravitational waves could teach them, even in the case of black-hole mergers.The detectors showed that immediately after the black holes merged, the waves quickly died down as the resulting black hole settled into a symmetrical shape. This is consistent with predictions made by theoretical physicist C. V. Vishveshwara in the early 1970s, a time when “gravitational waves and black holes both belonged to the realm of mythology”, he says. “At that time, I had not imagined that it would ever be verified,” says Vishveshwara, who is director emeritus of the Jawaharlal Nehru Planetarium in Bangalore, India. But LIGO saw only just over one cycle of the Event's ringdown waves before the signal became buried once more in the background noise — not yet enough data to provide a rigorous test of Vishveshwara's predictions. More-stringent tests will be possible if and when LIGO detects black-hole mergers that are larger than this one, or that occur closer to Earth than the Event's estimated distance of 1.3 billion light years, and thus give 'louder' waves that stay above the noise for longer. Alessandra Buonanno, a LIGO theorist and director of the Max Planck Institute for Gravitational Physics in Potsdam-Golm, Germany, says that a more detailed picture of the ringdown stage could reveal how fast the final black hole rotates, as well as whether its formation gave it a 'natal kick', imparting a high velocity. In addition, says Sathyaprakash, “we are especially waiting for systems that are much lighter, so they last longer”. Such events could include the mergers of lighter binary black holes, of binary neutron stars or of a black hole with a neutron star. Each type would deliver its own signature chirp, and could produce a signal that stays above LIGO's threshold of sensitivity for several minutes or more. “GW150914 is in some sense a very vanilla system,” says Chad Hanna, a LIGO member at Pennsylvania State University in University Park. “It's beautiful, of course, but it doesn't have all the crazy things that one might expect.” One phenomenon that Sathyaprakash is eager to observe is a 'precession' of the black holes' orbital plane, meaning that their paths trace a kind of 3D rosette. This is a relativistic effect that has no counterpart in Newtonian gravity, and it should produce a characteristic fluctuation in the strength of the gravitational waves. But orbital precession occurs only when two black holes have axes of rotation that point in random directions, and it disappears when the axes are both perpendicular to the orbital plane. The occurrence of a precession could provide clues to how the black holes formed. It's hard to be sure about that possibility because there are many uncertainties in simulating supernovas. But astrophysicists suspect that parallel spins generally signify that the original two stars were born together out of the same whirling gas cloud. Similarly, they think that random spins result from black holes that formed separately and later fell into orbit around each other. Once the observatories find more mergers, they may be able to determine which type of system occurs more frequently. Although detecting more events will help LIGO to do lots of science, its interferometers have intrinsic limitations that make it necessary to work together with a worldwide network of similar detectors that are now coming online. First, LIGO's two interferometers are not enough for scientists to determine precisely where the waves came from. The researchers can get some information by comparing the signal's time of arrival at each detector: the difference enables them to calculate the wave's direction relative to an imaginary line drawn between the two. But in the case of the Event, which recorded a difference of 6.9 milliseconds, their calculations limited the field of possibilities merely to a wide strip of southern sky. Had Virgo been online, the scientists could have narrowed down the direction substantially by comparing the waves' arrival times at three places. With a fourth interferometer (Japan is building an underground one called KAGRA, for Kamioka Gravitational-Wave Detector, and India has its own LIGO in planning), their precision would improve much more. Knowing an event's direction will in turn remove one of the biggest uncertainties in determining its distance from Earth. Waves that approach from a direction exactly perpendicular to the detector — either from above or from below, through Earth — will be recorded at their actual amplitude, explains Fulvio Ricci, a physicist at the University of Rome La Sapienza and the spokesperson for Virgo. Waves that come from elsewhere in the sky, however, will hit the detector at an angle and produce a somewhat smaller signal, according to a known formula. There are even some blind spots, where a source cannot be seen by a given detector at all. Determining the direction will therefore reveal the exact amplitude of the waves. By comparing that figure with the waves' amplitude at the source, which the researchers can derive from the shape of the signal, and by knowing how the amplitude decreases with distance, which they get from Einstein's theory, they can then calculate the distance of the source to a much higher precision. This situation is almost unprecedented: conventionally, astronomical distances need to be estimated by looking at the brightness of known objects in locations that range from the Solar System to distant galaxies. But the measured brightness of those 'standard candles' can be dimmed by stuff in between. Gravitational waves have no such limitation. There is another important reason why scientists are eager to have precise estimates of the waves' provenance. The LIGO and Virgo teams have arranged to give near-real-time alerts of intriguing events to more than 70 teams of conventional astronomers, who will use their optical, radio and space-based telescopes to see whether those events produced any form of electromagnetic radiation. In return, the LIGO and Virgo collaborations will be sifting through data to search for gravitational waves that could have been generated by events, such as supernova explosions, seen by the conventional observatories. Some 20 teams tried to follow up on the Event, mostly to no avail. NASA's Fermi Gamma-ray Space Telescope did see a possible burst of γ-rays about 0.4 seconds later, coming from an equally vague but compatible region of the southern sky4. But most observers now consider it to be a coincidence. Such γ-rays could, in principle, have been produced when gas orbiting the binary black hole was heated up during the merger, says Vicky Kalogera, a LIGO astrophysicist at Northwestern University in Evanston, Illinois. But “our astrophysical expectation has been that the gas from stars that formed the binary black hole has long dispersed. There shouldn't be any significant gas around”, she says. Going forward, however, matching gravitational waves with electromagnetic ones could usher in a new era of astronomy. In particular, mergers of neutron stars are expected to produce short γ-ray bursts. Researchers could then measure how far the light from those bursts is shifted towards the red end of the spectrum, which would tell astronomers how fast the stars' host galaxies are receding owing to the expansion of the Universe. Matching those redshifts to distance measurements calculated from gravitational waves should give estimates of the current rate of cosmic expansion, known as the Hubble constant, that are independent — and potentially more precise — than calculations using current methods. “From the point of view of measuring the Hubble constant, that's our gold-plated source”, says Holz. The LIGO and Virgo teams estimate that they have a 90% chance of finding more events in the data that LIGO has already collected. They are confident that by the time the next run finishes, the event count will be at least 5, growing to perhaps 35 by the end of a run scheduled to start in 2017. “To be honest,” says Holz, “I find it really hard to believe that the Universe is really doing this stuff. But it's not science fiction. It really happened.”

Researchers from the University of Liverpool's Institute of Translational Medicine have been awarded a grant of up to US$ 8.9 million (GBP £5.8m) to lead a multinational research consortium that aims to reduce mother-to-child transmission of HIV. The DolPHIN-2 investigators were funded as part of a major UNITAID initiative to gather evidence on the use of new priority antiretroviral regimens for first-line therapy in developing countries. . DolPHIN-2 seeks to reduce mother-to-child transmission of HIV during pregnancy, childbirth, and breastfeeding in women most at risk of transmitting the virus. Around 1.6 million women living with HIV become pregnant each year. Without antiretroviral therapy, the rates of mother-to-child transmission of HIV range from 15 to 45 per cent. With current HIV treatment this risk can be reduced to below five per cent, provided treatment is started early in pregnancy. However, a significant number of pregnant women in sub-Saharan Africa present late to maternity services, often in the last three months of pregnancy where current first-line therapy does not have sufficient time to act to prevent infant transmission. This late initiation of HIV treatment is associated with a seven-fold higher risk of infant transmission, and a doubling of infant mortality in the first year of life. A new drug, Dolutegravir (DTG), has the ability to act much more quickly than current recommended therapy. DTG rapidly reduces the amount of HIV in blood in the first three months of starting treatment, and thus potentially has considerable advantages in preventing infant transmission. However, the safety and efficacy of DTG in pregnant women is unknown, and this lack of knowledge is the major barrier to its widespread use in pregnancy. DolPHIN-2 comprises a large clinical trial in Uganda and South Africa, where late-presenting mothers are randomised to receive a DTG-containing regimen compared with standard-of-care treatment. Mothers and infants will be followed up for at least one year. Additional studies will examine the cost-effectiveness of implementing DTG across sub-Saharan Africa, identify and address the challenges the mothers face, and examine a number of factors which may enhance or prevent transmission. The DolPHIN-2 consortium is led by the University of Liverpool; other members include the Liverpool School of Tropical Medicine (LSTM), the Infectious Disease Institute in Kampala, the University of Cape Town and Radboud University Nijmegen. Professor Saye Khoo, Principle Investigator, University's Institute of Translational Medicine, said: "Mother-to-child transmission of HIV is preventable, and we have a duty to ensure the burden of HIV is not handed down across generations. Over 100,000 babies acquired HIV last year worldwide. "We have both a moral imperative to make new treatments available and affordable, and an ethical imperative to ensure these treatments are supported by robust evidence for safety and efficacy. As this evidence is gathered, we will work closely with international agencies involved in enlarging access and developing clinical guidelines in order to ensure that this research translates into real benefit for such a vulnerable population." UNITAID finds new and better ways to prevent, test and treat HIV, tuberculosis and malaria quickly and more affordably. It takes game-changing ideas and turns those into practical solutions that can help accelerate the end of the three diseases. Established in 2006 by Brazil, Chile, France, Norway and the United Kingdom, UNITAID plays an important part in the global effort to defeat HIV, tuberculosis and malaria. For more information please visit: http://www.

Van Geijlswijk I.M.,University Utrecht | Korzilius H.P.L.M.,Radboud University Nijmegen | Smits M.G.,Hospital Gelderse Vallei
Sleep | Year: 2010

Study Objectives: To perform a meta-analysis of the efficacy and safety of exogenous melatonin in advancing sleep-wake rhythm in patients with delayed sleep phase disorder. Design: Meta analysis of papers indexed for PubMed, Embase, and the abstracts of sleep and chronobiologic societies (1990-2009). Patients: Individuals with delayed sleep phase disorder. Interventions: Administration of melatonin. Measurements and Results: A meta-analysis of data of randomized controlled trials involving individuals with delayed sleep phase disorder that were published in English, compared melatonin with placebo, and reported 1 or more of the following: endogenous melatonin onset, clock hour of sleep onset, wake-up time, sleep-onset latency, and total sleep time. The 5 trials including 91 adults and 4 trials including 226 children showed that melatonin treatment advanced mean endogenous melatonin onset by 1.18 hours (95% confidence interval [CI]: 0.89-1.48 h) and clock hour of sleep onset by 0.67 hours (95% CI: 0.45-0.89 h). Melatonin decreased sleep-onset latency by 23.27 minutes (95% CI: 4.83 -41.72 min). The wake-up time and total sleep time did not change significantly. Conclusions: Melatonin is effective in advancing sleep-wake rhythm and endogenous melatonin rhythm in delayed sleep phase disorder.

Rajala N.,University of Tampere | Gerhold J.M.,Radboud University Nijmegen | Martinsson P.,University of Tampere | Klymov A.,Radboud University Nijmegen | And 2 more authors.
Nucleic Acids Research | Year: 2014

Mitochondrial DNA (mtDNA) is organized in discrete protein-DNA complexes, nucleoids, that are usually considered to be mitochondrial-inner-membrane associated. Here we addressed the association of replication factors with nucleoids and show that endogenous mtDNA helicase Twinkle and single-stranded DNA-binding protein, mtSSB, co-localize only with a subset of nucleoids. Using nucleotide analogs to identify replicating mtDNA in situ, the fraction of label-positive nucleoids that is Twinkle/mtSSB positive, is highest with the shortest labeling-pulse. In addition, the recruitment of mtSSB is shown to be Twinkle dependent. These proteins thus transiently associate with mtDNA in an ordered manner to facilitate replication. To understand the nature of mtDNA replication complexes, we examined nucleoid protein membrane association and show that endogenous Twinkle is firmly membrane associated even in the absence of mtDNA, whereas mtSSB and other nucleoid-associated proteins are found in both membrane-bound and soluble fractions. Likewise, a substantial amount of mtDNA is found as soluble or loosely membrane bound. We show that, by manipulation of Twinkle levels, mtDNA membrane association is partially dependent on Twinkle. Our results thus show that Twinkle recruits or is assembled with mtDNA at the inner membrane to form a replication platform and amount to the first clear demonstration that nucleoids are dynamic both in composition and concurrent activity. © 2013 The Author(s).

Sridhar S.S.,University of Toronto | Freedland S.J.,Duke University | Gleave M.E.,BC Cancer Agency | Higano C.,Seattle Cancer Center Alliance | And 4 more authors.
European Urology | Year: 2014

Context Until recently, the only approved agent for metastatic castration-resistant prostate cancer (mCRPC) was docetaxel chemotherapy. But over the last 5 years, significant advances in the field have led to the approval of five new agents, each with different mechanisms of action and demonstrating improved overall survival in separate randomized phase 3 trials. Many of these novel agents are now also being evaluated in earlier stages of the disease, which may ultimately lead to even better outcomes. Objective To summarize the current literature on the management of mCRPC with a particular focus on novel chemotherapy approaches, hormonal approaches, immunotherapy, and radiopharmaceuticals showing survival benefits in phase 3 clinical trials. Emerging therapies in late stages of development are also discussed briefly. Evidence acquisition A comprehensive search of PubMed, identified studies pertaining to novel therapies evaluated in mCRPC since the initial approval of docetaxel in 2004. Abstracts from major international meetings were hand searched to identify studies of novel agents in late stage development in mCRPC. The Clinical database was used to find ongoing clinical trials in the area of mCRPC. A detailed search of each new agent was also performed to ensure that additional trials of these agents in other stages of the disease were included where relevant. Evidence synthesis The main agents discussed are the androgen synthesis inhibitor abiraterone acetate, the androgen receptor inhibitor enzalutamide, the novel taxane chemotherapy cabazitaxel, the immunotherapy sipuleucel-T, and the radiopharmaceutical radium 223. Other emerging agents and a brief discussion of negative phase 3 results are also included. Conclusions It is a very exciting time in the field of mCRPC, where therapeutic advances have improved outcomes in this disease, although once metastatic overall median survival remains a dismal 2-3 years. The key now will be to understand how best to use these new agents, understand the mechanisms of resistance to them, continue to develop novel treatment strategies, and ultimately test these agents earlier in the disease when cure may be possible. © 2013 European Association of Urology.

Li B.,CAS Lanzhou Institute of Chemical Physics | Yu B.,CAS Lanzhou Institute of Chemical Physics | Huck W.T.S.,Radboud University Nijmegen | Zhou F.,CAS Lanzhou Institute of Chemical Physics | Liu W.,CAS Lanzhou Institute of Chemical Physics
Angewandte Chemie - International Edition | Year: 2012

Polymer brushes: Electrically induced atom-transfer radical polymerization allows polymer brushes to grow in air (see picture). The thickness of the brushes is controlled through the ratio of initiator and applied potential. The monomer solution can be reused, which renders this process promising for the polymerization of specialty monomers and for biocompatible polymer brushes grown on complex substrates. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Arts M.P.,Medical Center Haaglanden | Bartels R.H.M.A.,Radboud University Nijmegen
Spine Journal | Year: 2014

Background context The optimal surgical treatment of thoracic disc herniations remains controversial and depends on the consistency of the herniation and its location related to the spinal cord. Purpose To compare the outcomes of patients with symptomatic thoracic disc herniations treated with anterolateral mini-transthoracic approach (TTA) versus posterior transpedicular discectomy. Study design This is a prospective comparative cohort study. Patient sample One hundred consecutive patients with symptomatic thoracic herniated discs were operated by mini-TTA (56 patients) or transpedicular discectomy (44 patients). Outcome measures Neurologic assessment by American Spinal Injury Association (ASIA) Impairment Scale and patients' self reported perceived recovery and complications. Methods The consistency and location of the herniated disc in relation to the spinal cord was evaluated by preoperative computed tomography and magnetic resonance imaging. Patients were assessed neurologically before surgery and at regular outpatient controls at 2 months or later. Long-term follow-up was achieved by questionnaires sent by mail. Results In both groups, most patients had symptoms of myelopathy and radicular pain; patients who underwent mini-TTA, more frequently suffered from spasticity. Fifty-eight percent of the herniated discs were calcified and 77% were larger than one-third of the spinal canal. All patients presented with ASIA Grade C or D (64%) or ASIA Grade E (36%). Postoperatively, 50% of the patients treated with mini-TTA and 37% of the transpedicular group improved at least one grade on the ASIA scale (p=.19). The duration of surgery, blood loss, hospital stay, and complication rate were significantly higher in patients treated with mini-TTA and were mainly related to the magnitude and consistency of the herniated disc. At long-term follow-up, 72% of the mini-TTA patients reported good outcome versus 76% of the transpedicular discectomy group (p=.80). Conclusions Surgical treatment of a symptomatic herniated disc contributed to a clinical improvement in most cases. The approach is dependent on the location, the magnitude, and the consistency of the herniated thoracic disc. Medially located large calcified discs should be operated through an anterolateral approach, whereas noncalcified or lateral herniated discs can be treated from a posterior approach as well. For optimal treatment of this rare entity, the treatment should be performed in selected centers. © 2014 Elsevier Inc. All rights reserved.

Li B.,CAS Lanzhou Institute of Chemical Physics | Yu B.,CAS Lanzhou Institute of Chemical Physics | Huck W.T.S.,Radboud University Nijmegen | Liu W.,CAS Lanzhou Institute of Chemical Physics | Zhou F.,CAS Lanzhou Institute of Chemical Physics
Journal of the American Chemical Society | Year: 2013

Surface initiated atom transfer radical polymerization (SI-ATRP) was triggered after diffusion of a CuI/L activator generated at a working electrode. A stable [CuIIL]/[CuIL] ratio gradient was formed at the gap between the working electrode and the initiator terminated substrate due to ion diffusion. The size of the gap can be used to dictate polymer growth kinetics at different gap distances. Gradient polymer brushes were grafted when substrate was placed at a tilting angle along [Cu IIL]/[CuIL] gradient. © 2013 American Chemical Society.

Van Eldijk M.B.,Radboud University Nijmegen | McGann C.L.,University of Delaware | Kiick K.L.,University of Delaware | Van Hest J.C.M.,Radboud University Nijmegen
Topics in Current Chemistry | Year: 2012

Elastomeric polypeptides are very interesting biopolymers and are characterized by rubber-like elasticity, large extensibility before rupture, reversible deformation without loss of energy, and high resilience upon stretching. Their useful properties have motivated their use in a wide variety of materials and biological applications. This chapter focuses on elastin and resilin-two elastomeric biopolymers-and the recombinant polypeptides derived from them (elastin-like polypeptides and resilin-like polypeptides). This chapter also discusses the applications of these recombinant polypeptides in the fields of purification, drug delivery, and tissue engineering. © 2011 Springer-Verlag Berlin Heidelberg.

Helliwell P.S.,University of Leeds | Helliwell P.S.,Bradford Hospitals National Health Service NHS Foundation Trust | FitzGerald O.,Park University | Fransen J.,Radboud University Nijmegen
Journal of Rheumatology | Year: 2014

Objective. There are several new composite indices for assessing disease activity in psoriatic arthritis (PsA). Each may function as a disease state variable and a responder index. The aim of our study was to determine cutoffs for disease activity and response. Methods. Data from the Group for GRAPPA Composite Exercise (GRACE) study were used to develop cutoffs using a number of different approaches. Voting on choice of cutoff was undertaken at the 2013 GRAPPA Annual Meeting in Toronto, Ontario, Canada. Results. After voting, results for cutoffs for low/high disease activity for the Psoriatic ArthritiS Disease Activity Score (PASDAS), GRAppa Composite scorE (GRACE index), and Composite Psoriatic Disease Activity Index (CPDAI), respectively, were 3.2/5.4, 2.3/4.7, and 4/8. The measurement error for each composite score was estimated at 0.8, 1, and 2 for PASDAS, GRACE, and CPDAI, respectively. Conclusion. Response criteria for the new composite indices have been developed. These now require further validation and testing in other datasets.

Van Horssen R.,Radboud University Nijmegen | Ten Hagen T.L.,The Surgical Center
Journal of Cellular Physiology | Year: 2011

In our body cells move in three dimensions, embedded in an extracellular matrix that varies in composition, density and stiffness, and this movement is fundamental to life. Next to 3D cell migration assays, representing these physiological circumstances, still we need 2D migrations assays to perform detailed studies on the contribution of matrix-components and (extra)cellular proteins to cell movements. Next to the debate on differences between 3D and 2D migration, there also are many new perspectives on the use and development of novel or modified 2D cell migration assays. Of special significance is the introduction of so-called barrier migration assays, methods that avoid cell and matrix damage, as complementation or replacement of scratch/wound healing assays. Here, we discuss the possibilities and limitations of different 2D barrier migration assays. © 2010 Wiley-Liss, Inc.

Polderman T.J.C.,VU University Amsterdam | Benyamin B.,University of Queensland | De Leeuw C.A.,VU University Amsterdam | De Leeuw C.A.,Radboud University Nijmegen | And 5 more authors.
Nature Genetics | Year: 2015

Despite a century of research on complex traits in humans, the relative importance and specific nature of the influences of genes and environment on human traits remain controversial. We report a meta-analysis of twin correlations and reported variance components for 17,804 traits from 2,748 publications including 14,558,903 partly dependent twin pairs, virtually all published twin studies of complex traits. Estimates of heritability cluster strongly within functional domains, and across all traits the reported heritability is 49%. For a majority (69%) of traits, the observed twin correlations are consistent with a simple and parsimonious model where twin resemblance is solely due to additive genetic variation. The data are inconsistent with substantial influences from shared environment or non-additive genetic variation. This study provides the most comprehensive analysis of the causes of individual differences in human traits thus far and will guide future gene-mapping efforts. All the results can be visualized using the MaTCH webtool. © 2015 Nature America, Inc. All rights reserved.

Alexander S.,University of Houston | Weigelin B.,Radboud University Nijmegen | Winkler F.,German Cancer Research Center | Friedl P.,University of Houston | And 2 more authors.
Current Opinion in Cell Biology | Year: 2013

Key steps of cancer progression and therapy response depend upon interactions between cancer cells with the reactive tumour microenvironment. Intravital microscopy enables multi-modal and multi-scale monitoring of cancer progression as a dynamic step-wise process within anatomic and functional niches provided by the microenvironment. These niches deliver cell-derived and matrix-derived signals that enable cell subsets or single cancer cells to survive, migrate, grow, undergo dormancy, and escape immune surveillance. Beyond basic research, intravital microscopy has reached preclinical application to identify mechanisms of tumour-stroma interactions and outcome. We here summarise how n-dimensional 'dynamic histopathology' of tumours by intravital microscopy shapes mechanistic insight into cell-cell and cell-tissue interactions that underlie single-cell and collective cancer invasion, metastatic seeding at distant sites, immune evasion, and therapy responses. © 2013 Elsevier Ltd.

Gow N.A.R.,Aberdeen Group | Netea M.G.,Radboud University Nijmegen
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2016

Fungi cause more than a billion skin infections, more than 100 million mucosal infections, 10 million serious allergies and more than a million deaths each year. Global mortality owing to fungal infections is greater than for malaria and breast cancer and is equivalent to that owing to tuberculosis (TB) and HIV. These statistics evidence fungal infections as a major threat to human health and a major burden to healthcare budgets worldwide. Those patients who are at greatest risk of life-threatening fungal infections include those who have weakened immunity or have suffered trauma or other predisposing infections such as HIV. To address these global threats to human health, more research is urgently needed to understand the immunopathology of fungal disease and human disease susceptibility in order to augment the advances being made in fungal diagnostics and drug development. Here, we highlight some recent advances in basic research in medical mycology and fungal immunology that are beginning to inform clinical decisions and options for personalized medicine, vaccine development and adjunct immunotherapies. © 2016 The Authors.

Cambi A.,Radboud University Nijmegen | Lidke D.S.,University of New Mexico
ACS Chemical Biology | Year: 2012

Understanding the molecular mechanisms that shape an effective cellular response is a fundamental question in biology. Biochemical measurements have revealed critical information about the order of protein - protein interactions along signaling cascades but lack the resolution to determine kinetics and localization of interactions on the plasma membrane. Furthermore, the local membrane environment influences membrane receptor distributions and dynamics, which in turn influences signal transduction. To measure dynamic protein interactions and elucidate the consequences of membrane architecture interplay, direct measurements at high spatiotemporal resolution are needed. In this review, we discuss the biochemical principles regulating membrane nanodomain formation and protein function, ranging from the lipid nanoenvironment to the cortical cytoskeleton. We also discuss recent advances in fluorescence microscopy that are making it possible to quantify protein organization and biochemical events at the nanoscale in the living cell membrane. © 2011 American Chemical Society.

Castel D.,Institute Pasteur Paris | Mourikis P.,Institute Pasteur Paris | Bartels S.J.J.,Radboud University Nijmegen | Brinkman A.B.,Radboud University Nijmegen | And 2 more authors.
Genes and Development | Year: 2013

Notch signaling plays crucial roles in mediating cell fate choices in all metazoans largely by specifying the transcriptional output of one cell in response to a neighboring cell. The DNA-binding protein RBPJ is the principle effector of this pathway in mammals and, together with the transcription factor moiety of Notch (NICD), regulates the expression of target genes. The prevalent view presumes that RBPJ statically occupies consensus binding sites while exchanging repressors for activators in response to NICD. We present the first specific RBPJ chromatin immunoprecipitation and high-throughput sequencing study in mammalian cells. To dissect the mode of transcriptional regulation by RBPJ and identify its direct targets, whole-genome binding profiles were generated for RBPJ; its coactivator, p300; NICD; and the histone H3 modifications H3 Lys 4 trimethylation (H3K4me3), H3 Lys 4 monomethylation (H3K4me1), and histone H3 Lys 27 acetylation (H3K27ac) in myogenic cells under active or inhibitory Notch signaling conditions. Our results demonstrate dynamic binding of RBPJ in response to Notch activation at essentially all sites co-occupied by NICD. Additionally, we identify a distinct set of sites where RBPJ recruits neither NICD nor p300 and binds DNA statically, irrespective of Notch activity. These findings significantly modify our views on how RBPJ and Notch signaling mediate their activities and consequently impact on cell fate decisions. © 2013 by Cold Spring Harbor Laboratory Press.

Brown G.D.,Aberdeen Group | Netea M.G.,Radboud University Nijmegen
Cell Host and Microbe | Year: 2012

The last decade has brought significant advances in our understanding of antifungal immunity, which offer hope for the development of novel immunotherapeutics. In this commentary, we provide a snapshot of the protective innate and adaptive components of antifungal immunity and highlight several recent topics of interest, placing in context the three associated reviews in this issue of Cell Host & Microbe. © 2012 Elsevier Inc.

Brown A.J.P.,Aberdeen Group | Brown G.D.,Aberdeen Group | Netea M.G.,Radboud University Nijmegen | Gow N.A.R.,Aberdeen Group
Trends in Microbiology | Year: 2014

Metabolism is integral to the pathogenicity of Candida albicans, a major fungal pathogen of humans. As well as providing the platform for nutrient assimilation and growth in diverse host niches, metabolic adaptation affects the susceptibility of C. albicans to host-imposed stresses and antifungal drugs, the expression of key virulence factors, and fungal vulnerability to innate immune defences. These effects, which are driven by complex regulatory networks linking metabolism, morphogenesis, stress adaptation, and cell wall remodelling, influence commensalism and infection. Therefore, current concepts of Candida-host interactions must be extended to include the impact of metabolic adaptation upon pathogenicity and immunogenicity. © 2014 The Authors.

Bastos A.M.,Ernst Strüngmann Institute (ESI) for Neuroscience | Bastos A.M.,Massachusetts Institute of Technology | Vezoli J.,Ernst Strüngmann Institute (ESI) for Neuroscience | Fries P.,Ernst Strüngmann Institute (ESI) for Neuroscience | Fries P.,Radboud University Nijmegen
Current Opinion in Neurobiology | Year: 2015

The communication-through-coherence (CTC) hypothesis proposes that anatomical connections are dynamically rendered effective or ineffective through the presence or absence of rhythmic synchronization, in particular in the gamma and beta bands. The original CTC statement proposed that uni-directional communication is due to rhythmic entrainment with an inter-areal delay and a resulting non-zero phase relation, whereas bi-directional communication is due to zero-phase synchronization. Recent studies found that inter-areal gamma-band synchronization entails a non-zero phase lag. We therefore modify the CTC hypothesis and propose that bi-directional cortical communication is realized separately for the two directions by uni-directional CTC mechanisms entailing delays in both directions. We review evidence suggesting that inter-areal influences in the feedforward and feedback directions are segregated both anatomically and spectrally. © 2014.

Banks P.A.,Harvard University | Bollen T.L.,St Antonius Hospital | Dervenis C.,Agia Olga Hospital | Gooszen H.G.,Radboud University Nijmegen | And 4 more authors.
Gut | Year: 2013

Background and objective: The Atlanta classification of acute pancreatitis enabled standardised reporting of research and aided communication between clinicians. Deficiencies identified and improved understanding of the disease make a revision necessary. Methods: A web-based consultation was undertaken in 2007 to ensure wide participation of pancreatologists. After an initial meeting, the Working Group sent a draft document to 11 national and international pancreatic associations. This working draft was forwarded to all members. Revisions were made in response to comments, and the web-based consultation was repeated three times. The final consensus was reviewed, and only statements based on published evidence were retained. Results: The revised classi fication of acute pancreatitis identified two phases of the disease: early and late. Severity is classified as mild, moderate or severe. Mild acute pancreatitis, the most common form, has no organ failure, local or systemic complications and usually resolves in the first week. Moderately severe acute pancreatitis is defined by the presence of transient organ failure, local complications or exacerbation of co-morbid disease. Severe acute pancreatitis is defined by persistent organ failure, that is, organ failure >48 h. Local complications are peripancreatic fluid collections, pancreatic and peripancreatic necrosis (sterile or infected), pseudocyst and walled-off necrosis (sterile or infected). We present a standardised template for reporting CT images. Conclusions: This international, web-based consensus provides clear de finitions to classify acute pancreatitis using easily identified clinical and radiologic criteria. The wide consultation among pancreatologists to reach this consensus should encourage widespread adoption.

Yuan S.,Radboud University Nijmegen | De Raedt H.,Zernike Institute for Advanced Materials | Katsnelson M.I.,Radboud University Nijmegen
Physical Review B - Condensed Matter and Materials Physics | Year: 2010

We present a detailed numerical study of the electronic transport properties of bilayer and trilayer graphene within a framework of single-electron tight-binding model. Various types of disorder are considered, such as resonant (hydrogen) impurities, vacancies, short- or long-range Gaussian random potentials, and Gaussian random nearest-neighbor hopping. The algorithms are based on the numerical solution of the time-dependent Schrödinger equation and applied to calculate the density of states and conductivities (via the Kubo formula) of large samples containing millions of atoms. In the cases under consideration, far enough from the neutrality point, depending on the strength of disorders and the stacking sequence, a linear or sublinear electron-density-dependent conductivity is found. The minimum conductivity σ min ≈ 2 e2 /h (per layer) at the charge neutrality point is the same for bilayer and trilayer graphene, independent of the type of the impurities, but the plateau of minimum conductivity around the neutrality point is only observed in the presence of resonant impurities or vacancies, originating from the formation of the impurity band. © 2010 The American Physical Society.

Yuan S.,Radboud University Nijmegen | De Raedt H.,Zernike Institute for Advanced Materials | Katsnelson M.I.,Radboud University Nijmegen
Physical Review B - Condensed Matter and Materials Physics | Year: 2010

We present a detailed numerical study of the electronic properties of single-layer graphene with resonant (hydrogen) impurities and vacancies within a framework of noninteracting tight-binding model on a honeycomb lattice. The algorithms are based on the numerical solution of the time-dependent Schrödinger equation and applied to calculate the density of states, quasieigenstates, ac and dc conductivities of large samples containing millions of atoms. Our results give a consistent picture of evolution of electronic structure and transport properties of functionalized graphene in a broad range of concentration of impurities (from graphene to graphane), and show that the formation of impurity band is the main factor determining electrical and optical properties at intermediate impurity concentrations, together with a gap opening when approaching the graphane limit. © 2010 The American Physical Society.

Hedayat M.,Tehran University of Medical Sciences | Netea M.G.,Radboud University Nijmegen | Rezaei N.,Tehran University of Medical Sciences | Rezaei N.,University of Sheffield
The Lancet Infectious Diseases | Year: 2011

Toll-like receptors (TLRs) recognise highly conserved molecular structures, collectively known as pathogen-associated molecular patterns. In the past two decades, development and clinical implementation of TLR ligands-ie, chemically modified synthetic derivatives of naturally occurring ligands and fully synthetic small molecules-have been topics of intense research. Targeted manipulation of TLR signalling has been applied clinically to boost vaccine effectiveness, promote a robust T helper 1-predominant immune response against viral infection, or dampen the exaggerated inflammatory response to bacterial infection. Use of these new therapeutic molecules as adjuncts to conventional pharmacotherapy or stand-alone treatments might offer solutions to unmet clinical needs or could replace existing partly effective therapeutic strategies. © 2011 Elsevier Ltd.

Yildirim B.O.,De Kluyskamp | Derksen J.J.L.,Radboud University Nijmegen
Psychiatry Research | Year: 2012

Life-course persistent antisocial behavior is 10 to 14 times more prevalent in males and it has been suggested that testosterone levels could account for this gender bias. Preliminary studies with measures of fetal testosterone find inconsistent associations with antisocial behavior, especially studies that use the 2D:4D ratio as a proxy for fetal testosterone. However, circulating testosterone consistently shows positive associations with antisocial behaviors throughout childhood, adolescence, and adulthood, particularly in males. It is suggested that high fetal/circulating testosterone interactively influence the maturation and functionality of mesolimbic dopaminergic circuitry, right orbitofrontal cortex, and cortico-subcortical connectivity, resulting in a strong reward motivation, low social sensitivity, and dampened regulation of strong motivational/emotional processes. The link between these testosterone induced endophenotypes and actual display of antisocial behavior is strongly modulated by different social (e.g., social rejection, low SES) and genetic (e.g., MAOA, 5HTT) risk factors that can disturb socio-, psycho-, and biological development and interact with testosterone in shaping behavior. When these additional risk factors are present, the testosterone induced endophenotypes may increase the risk for a chronic antisocial lifestyle. However, behavioral endophenotypes induced by testosterone can also predispose towards socially adaptive traits such as a strong achievement motivation, leadership, fair bargaining behaviors, and social assertiveness. These adaptive traits are more likely to emerge when the high testosterone individual has positive social experiences that promote prosocial behaviors such as strong and secure attachments with his caregivers, affiliation with prosocial peers, and sufficient socioeconomic resources. A theoretical model is presented, various hypotheses are examined, and future venues for research are discussed. © 2012 Elsevier Ireland Ltd.

Dugaev V.K.,Rzeszow University of Technology | Katsnelson M.I.,Radboud University Nijmegen
Physical Review B - Condensed Matter and Materials Physics | Year: 2014

We discuss the role of spin-flip scattering of electrons from the magnetized edges in graphene nanoribbons. The spin-flip scattering is associated with strong fluctuations of the magnetic moments at the edge. Using the Boltzmann equation approach, which is valid for not too narrow nanoribbons, we calculate the spin-relaxation time in the case of Berry-Mondragon and zigzag graphene edges. We also consider the case of ballistic nanoribbons characterized by very long momentum relaxation time in the bulk, when the main source of momentum and spin relaxation is the spin-dependent scattering at the edges. We found that in the case of zigzag edges, an anomalous spin diffusion is possible, which is related to very weak spin-flip scattering of electrons gliding along the nanoribbon edge. © 2014 American Physical Society.

Kleiss R.,Radboud University Nijmegen | Van Den Oord G.,NIKHEF
Computer Physics Communications | Year: 2011

We present a new Monte Carlo tool that computes full tree-level matrix elements in high-energy physics. The program accepts user-defined models and has no restrictions on the process multiplicity. To achieve acceptable performance, CAMORRA evaluates the matrix elements in a recursive way by combining off-shell currents. Furthermore, CAMORRA can be used to compute amplitudes involving continuous color and helicity final states. © 2010 Elsevier B.V. All rights reserved.

Endrass T.,Otto Von Guericke University of Magdeburg | Endrass T.,Center for Behavioral Brain science | Ullsperger M.,Otto Von Guericke University of Magdeburg | Ullsperger M.,Center for Behavioral Brain science | Ullsperger M.,Radboud University Nijmegen
Neuroscience and Biobehavioral Reviews | Year: 2014

Obsessive-compulsive disorder (OCD) is characterized by overactivity in frontal and striatal brain regions, and event-related potential studies have shown increased brain activity during performance monitoring. The error-related negativity (ERN) is a component of the event-related potential that is observed following incorrect responses, and signals the need for behavioral adjustments. ERN enhancements have even been considered as a biomarker or endophenotype of OCD. However over the past years, enhanced ERN amplitudes, although less reliably, were also found in anxiety and affective disorders. These results question the specificity of ERN alterations to OCD. The present review summarizes current findings on performance monitoring and feedback processing in OCD and their relation to behavioral measures. Further, it discusses possible differential mechanisms contributing to amplitude variations in different clinical conditions. © 2014 Elsevier Ltd.

Homberg J.R.,Radboud University Nijmegen | Molteni R.,University of Milan | Calabrese F.,University of Milan | Riva M.A.,University of Milan
Neuroscience and Biobehavioral Reviews | Year: 2014

Serotonin (5-HT) and brain-derived neurotrophin factor (BDNF) are known to modulate behavioral responses to stress and to mediate the therapeutic efficacy of antidepressant agents through neuroplastic and epigenetic mechanisms. While the two systems interact at several levels, this scenario is complicated by a number of variants including brain region specificity, 5-HT receptor selectivity and timing. Based on recent insights obtained using 5-HT transporter (5-HTT) knockout rats we here set-out and discuss the crucial role of neurodevelopmental mechanisms and the contribution of transcription factors and epigenetic modifications to this interaction and its variants. 5-HTT knockout in rats, as well as the low activity short allelic variant of the serotonin transporter human polymorphism, consistently show reduced BDNF mRNA and protein levels in the hippocampus and in the prefrontal cortex. This starts during the second postnatal week, is preceded by DNA hypermethylation during the first postnatal week, and it is developmentally paralleled by reduced expression of key transcription factors. The reduced BDNF levels, in turn, affect 5-HT1A receptor-mediated intracellular signaling and thereby the serotonergic phenotype of the neurons. We propose that such a negative spiral of modifications may affect brain development and reduce its resiliency to environmental challenges during critical time windows, which may lead to phenotypic alterations that persist for the entire life. The characterization of 5-HT-BDNF interactions will eventually increase the understanding of mental illness etiology and, possibly, lead to the identification of novel molecular targets for drug development. © 2014 Elsevier Ltd.

Ullsperger M.,Otto Von Guericke University of Magdeburg | Ullsperger M.,Center for Behavioral Brain science | Ullsperger M.,Radboud University Nijmegen | Fischer A.G.,Otto Von Guericke University of Magdeburg | And 5 more authors.
Trends in Cognitive Sciences | Year: 2014

Successful goal-directed behavior critically depends on performance monitoring, a set of cognitive and affective functions determining whether adaptive control is needed and, if so, which type and magnitude is required. Knowledge of the brain structures involved in such a process has grown enormously, although the time course of performance-monitoring (PM) activity remains poorly understood. Here, we review evidence from EEG recordings in humans and show that monitored events elicit a rather uniform sequence of cortical activity reflecting the detection, accumulation, and weighting of evidence for the necessity to adapt and (re)act. We link the EEG findings with invasive and pharmacological findings and evaluate the neurobiological plausibility of current theories of PM. © 2014 Elsevier Ltd.

Micali N.,CNR Institute for Chemical and Physical Processes | Engelkamp H.,Radboud University Nijmegen | Van Rhee P.G.,Radboud University Nijmegen | Christianen P.C.M.,Radboud University Nijmegen | And 2 more authors.
Nature Chemistry | Year: 2012

Many essential biological molecules exist only in one of two possible mirror-image structures, either because they possess a chiral unit or through their structure (helices, for example, are intrinsically chiral), but so far the origin of this homochirality has not been unraveled. Here we demonstrate that the handedness of helical supramolecular aggregates formed by achiral molecules can be directed by applying rotational, gravitational and orienting forces during the self-assembly process. In this system, supramolecular chirality is determined by the relative directions of rotation and magnetically tuned effective gravity, but the magnetic orientation of the aggregates is also essential. Applying these external forces only during the nucleation step of the aggregation is sufficient to achieve chiral selection. This result shows that an almost instantaneous chiral perturbation can be transferred and amplified in growing supramolecular self-assemblies, and provides evidence that a falsely chiral influence is able to induce absolute enantioselection.© 2012 Macmillan Publishers Limited. All rights reserved.

Garlanda C.,Humanitas Clinical and Research Center | Dinarello C.A.,Aurora University | Dinarello C.A.,Radboud University Nijmegen | Mantovani A.,Humanitas Clinical and Research Center | Mantovani A.,University of Milan
Immunity | Year: 2013

Interleukin-1 (IL-1) is a central mediator of innate immunity and inflammation. The IL-1 family includes seven ligands with agonist activity (IL-1α and IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ), three receptor antagonists (IL-1Ra, IL-36Ra, IL-38), and an anti-inflammatory cytokine (IL-37). Members of the IL-1 Receptor (IL-1R) family include six receptor chains forming four signaling receptor complexes, two decoy receptors (IL-1R2, IL-18BP), and two negative regulators (TIR8 or SIGIRR, IL-1RAcPb). A tight regulation via receptor antagonists, decoy receptors, and signaling inhibitors ensures a balance between amplification of innate immunity and uncontrolled inflammation. All cells of the innate immune system express and/or are affected by IL-1 family members. Moreover, IL-1 family members play a key role in the differentiation and function of polarized innate and adaptive lymphoid cells. Here we will review the key properties of IL-1 family members, with emphasis on pathways of negative regulation and orchestration of innate and adaptive immunity. © 2013 Elsevier Inc.

Vergeer P.,University of Leeds | Vergeer P.,Radboud University Nijmegen | Kunin W.E.,University of Leeds
New Phytologist | Year: 2013

Widely distributed species, such as the perennial plant Arabidopsis lyrata, face a range of environmental conditions across space, creating selective pressures for local evolutionary adaptation. The species' fragmented distribution may reduce gene flow, which could either reduce or increase adaptive potential. The substantial variation in phenotypic traits observed across this species' northwestern European range may reflect a combination of plastic responses to environmental conditions, evolutionary adaptation and nonadaptive genetic differentiation. We conducted multi-site common garden experiments to study differences in plant performance in core and marginal areas. Plants from eight source populations representing the species' full geographic and altitudinal range in northwestern Europe were planted out in Iceland, Sweden, Scotland and Wales. We found evidence of both strong plastic responses and apparently adaptive differentiation in performance. Most evidence for local adaptation was found at range margins, with the strongest effects on reproductive output. Both biotic and abiotic factors affected performance, especially at range margins. Performance of most plants was best in the Scottish and Swedish common garden sites, in the core of the species' distribution. Despite adaptations at range margins, the performance of the species declines at distributional limits, with extreme southern populations looking particularly vulnerable. © 2012 The Authors. New Phytologist © 2012 New Phytologist Trust.

Yildirim B.O.,De Kluyskamp | Derksen J.J.L.,Radboud University Nijmegen
Psychiatry Research | Year: 2012

Testosterone (T) has received increasing interest in the recent years as a probable biological determinant in the etiology of male-biased clinical conditions such as psychopathy (i.e. psychopathy is more prevalent in men and leads to an earlier onset and more severe expression of antisocial and aggressive behavior in men compared to women). In this review, the authors evaluated the potential relationship between T and different constructs closely related to the core characteristics of psychopathy (affective empathy, fear-reactivity, and instrumental aggression). After a thorough examination of the literature, it is concluded that high T exposure in utero and high circulating T levels throughout important life phases (most notably adolescence) or in response to social challenges (e.g. social stress, competition) could be an important etiological risk factor in the emergence of psychopathic behavior. Nevertheless, studies consistently indicate that high T is not related to a significantly reduced fear-reactivity and is only indirectly associated with the increased levels of instrumental aggression observed in psychopathic individuals. Therefore, psychopathy is likely to arise from an interaction between high T levels and other biological and socio-psychological risk factors, such as a constitutionally based dampened fear-reactivity, insecure/disordered attachment processes in childhood, and social discrimination/rejection in adolescence and/or adulthood. © 2012 Elsevier Ltd.

Das R.K.,Radboud University Nijmegen | Zouani O.F.,Parc Unitec 1
Biomaterials | Year: 2014

Physicochemical features of a cell nanoenvironment exert important influence on stem cell behavior and include the influence of matrix elasticity and topography on differentiation processes. The presence of growth factors such as TGF-β and BMPs on these matrices provides chemical cues and thus plays vital role in directing eventual stem cell fate. Engineering of functional biomimetic scaffolds that present programmed spatio-temporal physical and chemical signals to stem cells holds great promise in stem cell therapy. Progress in this field requires tacit understanding of the mechanistic aspects of cell-environment nanointeractions, so that they can be manipulated and exploited for the design of sophisticated next generation biomaterials. In this review, we report and discuss the evolution of these processes and pathways in the context of matrix adhesion as they might relate to stemness and stem cell differentiation. Super-resolution microscopy and single-molecule methods for invitro nano-manipulation are helping to identify and characterize the molecules and mechanics of structural transitions within stem cells and matrices. All these advances facilitate research toward understanding of stem cell niche and consequently to developing new class of biomaterials helping the "used biomaterials" for applications in tissue engineering and regenerative medicine. © 2014 Elsevier Ltd.

Nagtegaal I.D.,Radboud University Nijmegen | Quirke P.,University of Leeds | Schmoll H.-J.,Martin Luther University of Halle Wittenberg
Nature Reviews Clinical Oncology | Year: 2012

In 2009, the Union for International Cancer Control issued the seventh edition of the well-used T (tumor), N (node), and M (metastasis) classification guidelines. There has been a continual refinement of the staging for colorectal cancer since this system for assessing tumor stage was initially adopted and it has been used to guide treatment decisions for over 50 years. However, the outcome after therapy for patients with colorectal cancer is very variable, even when patients are assigned to the same TNM category. This article assesses the changes that have been made since the sixth edition and discusses whether they are, in fact, informative improvements for a practicing clinician. © 2012 Macmillan Publishers Limited. All rights reserved.

Coates L.C.,University of Leeds | Fransen J.,Radboud University Nijmegen | Helliwell P.S.,University of Leeds
Annals of the Rheumatic Diseases | Year: 2010

Objective: To create minimal disease activity (MDA) criteria for psoriatic arthritis (PsA). With recent therapeutic advances, this is now a goal for treatment and may represent a measure to compare therapies. It defines a satisfactory state of disease activity rather than a change, and encompasses all aspects of the disease. Methods: 40 patient profiles were sampled from an observational PsA database. Sixty experts in PsA classified these as in MDA or not. A consensus of ≥70% was accepted, identifying 13 profiles in MDA. Summary statistics created possible cut-off points for the definition. Considering the number of measures that must be met, 35 candidate definitions were created and tested using receiver operating characteristic curves (ROC) for sensitivity and specificity. Results: Four candidate definitions showed high area under the curve values on ROC testing. Definitions with high outlying values were excluded as they were not considered to represent MDA. Aiming for high specificity to reduce false positives resulted in a preference for the following definition: "A patient is classified as achieving MDA when meeting 5 of the 7 following criteria: tender joint count ≤1; swollen joint count ≤1; Psoriasis Activity and Severity Index ≤1 or body surface area ≤3; patient pain visual analogue score (VAS) ≤15; patient global disease activity VAS ≤20; health assessment questionnaire ≤0.5; tender entheseal points (1". Conclusion: This study provides the first definition of a "state" of MDA in PsA and defines a target for treatment. It must now be validated in other populations and tested in clinical trials.

University of Utah and Radboud University Nijmegen | Date: 2014-08-19

An ultrasound transducer system. The system includes at least three ultrasound transducer arrays including a central transducer array and at least two lateral transducer arrays located adjacent the central transducer array, wherein the at least three ultrasound transducer arrays are arranged such that ultrasound beam paths of the at least three ultrasound transducer arrays overlap in an approximately planar location.

Kuss D.J.,Nottingham Trent University | Louws J.,Radboud University Nijmegen | Wiers R.W.,University of Amsterdam
Cyberpsychology, Behavior, and Social Networking | Year: 2012

Recently, there have been growing concerns about excessive online gaming. Playing Massively Multiplayer Online Role-Playing Games (MMORPGs) appears to be particularly problematic, because these games require a high degree of commitment and time investment from the players to the detriment of occupational, social, and other recreational activities and relations. A number of gaming motives have been linked to excessive online gaming in adolescents and young adults. We assessed 175 current MMORPG players and 90 nonplayers using a Web-based questionnaire regarding their gaming behavior, problems as consequences of gaming, and game motivations and tested their statistical associations. Results indicated that (a) MMORPG players are significantly more likely to experience gaming-related problems relative to nonplayers, and that (b) the gaming motivations escapism and mechanics significantly predicted excessive gaming and appeared as stronger predictors than time investment in game. The findings support the necessity of using measures that distinguish between different types of online games. In addition, this study proves useful regarding the current discussion on establishing (online) gaming addiction as a diagnosis in future categorizations of psychopathology. © Copyright 2012, Mary Ann Liebert, Inc.

Cook J.L.,Radboud University Nijmegen | Cook J.L.,City University London
Neuroscience and Biobehavioral Reviews | Year: 2014

Contrary to the prevailing view, Nicolle and colleagues (2012) recently demonstrated that dorsal and ventral regions of the medial prefrontal cortex (mPFC) and temporoparietal cortex (TPC) do not distinguish between action values relating to the self and to another individual; rather, these regions differentiate whether an action is currently relevant or irrelevant to the task at hand. This finding suggests solutions to paradoxes in social cognition. The first paradox concerns self/other control: With some experimental tasks TPC activity is associated with the promotion of self over other representations; in different tasks the association is with other over self (Santiesteban et al., 2012a). The second paradox concerns the control of imitation: MPFC has been associated with both the facilitation and inhibition of imitation. Considering task-relevance (i.e. whether the participant's task is to respond according to their own action values or to respond as if they were another individual) suggests possible solutions to these paradoxes. © 2014 Elsevier Ltd.

Huuskonen A.,Finnish Meteorological Institute | Saltikoff E.,Finnish Meteorological Institute | Holleman I.,Radboud University Nijmegen
Bulletin of the American Meteorological Society | Year: 2014

The operational weather radar network in Europe covers more than 30 countries and contains more than 200 weather radars. The radar network is heterogeneous in hardware, signal processing, transmit/receive frequency, and scanning strategy, thus making it fundamentally different than the Next Generation Weather Radar (NEXRAD) network. Within the European National Meteorological Services (EUMETNET), a grouping of services, the Operational Program for Exchange of Weather Radar Information (OPERA) has been working since 1999 on improving the harmonization of radars and their measurements. In addition, OPERA has facilitated and stimulated the exchange of radar data between its members, among others, by the development of a radar data information model and jointly agreed data formats. Since 2011, a radar data center has been in operation, producing network-wide radar mosaics from volumetric data. An essential part of the OPERA work is the documentation of the members' best practices in radar operation and data production and the making of joint recommendations.

Barentsz J.O.,Radboud University Nijmegen | Thoeny H.C.,University of Bern
Nature Reviews Urology | Year: 2015

Most metastatic lymph nodes in patients with prostate cancer go undetected by current imaging techniques and limited pelvic lymph node dissection (PLND), as they are small and located in difficult-to-reach areas. As the only current alternative is an extended PLND, the search for more accurate imaging techniques continues. © 2015 Macmillan Publishers Limited. All rights reserved.

Friedl P.,Radboud University Nijmegen | Friedl P.,University of Houston | Sahai E.,Cancer Research UK Research Institute | Weiss S.,University of Michigan | Yamada K.M.,U.S. National Institutes of Health
Nature Reviews Molecular Cell Biology | Year: 2012

Studies of cell migration in three-dimensional (3D) cell culture systems and in vivo have revealed several differences when compared with cell migration in two dimensions, including their morphology and mechanical and signalling control. Here, researchers assess the contribution of 3D models to our understanding of cell migration, both in terms of the mechanisms used to drive single cell and collective cell migration and how migrating cells respond to a changing environment in vivo. © 2012 Macmillan Publishers Limited. All rights reserved.

Van Strien T.,Radboud University Nijmegen | Peter Herman C.,University of Toronto | Anschutz D.,Radboud University Nijmegen
International Journal of Eating Disorders | Year: 2012

Objective: To challenge the conclusion by Jansen et al., Int J Eat Disord 2011; 44:164-168, that the widely used Dutch Eating Behavior Questionnaire (DEBQ) External Eating subscale (DEBQ-EX) lacks validity for external eating, because of limitations of that study. Method: In a seminaturalistic setting we measured participants' intake of crisps and M&Ms while they watched food commercials or neutral commercials spliced into a film. To avoid misclassification due to the use of median splits we used extreme scores on the DEBQ-ex (n = 60) in addition to the full range of scores (n = 125). Results: As was expected, high external eaters in the food commercial condition ate more crisps than did high external eaters in the neutral commercial condition, whereas low external eaters did not eat more crisps in one condition than in the other. No such moderator effect was found for emotional eating. No significant moderator effect was found for external eating in the original sample (n = 125) using the median-split procedure. Discussion: The DEBQ scale for external eating has validity and specificity for external eating provided that the participants have sufficiently extreme external eating scores and a natural setting is used. © 2011 by Wiley Periodicals, Inc.

Groenwold R.H.H.,University Utrecht | Donders A.R.T.,Radboud University Nijmegen | Roes K.C.B.,University Utrecht | Harrell Jr. F.E.,Vanderbilt University | Moons K.G.M.,University Utrecht
American Journal of Epidemiology | Year: 2012

Although missing outcome data are an important problem in randomized trials and observational studies, methods to address this issue can be difficult to apply. Using simulated data, the authors compared 3 methods to handle missing outcome data: 1) complete case analysis; 2) single imputation; and 3) multiple imputation (all 3 with and without covariate adjustment). Simulated scenarios focused on continuous or dichotomous missing outcome data from randomized trials or observational studies. When outcomes were missing at random, single and multiple imputations yielded unbiased estimates after covariate adjustment. Estimates obtained by complete case analysis with covariate adjustment were unbiased as well, with coverage close to 95%. When outcome data were missing not at random, all methods gave biased estimates, but handling missing outcome data by means of 1 of the 3 methods reduced bias compared with a complete case analysis without covariate adjustment. Complete case analysis with covariate adjustment and multiple imputation yield similar estimates in the event of missing outcome data, as long as the same predictors of missingness are included. Hence, complete case analysis with covariate adjustment can and should be used as the analysis of choice more often. Multiple imputation, in addition, can accommodate the missing-not-at-random scenario more flexibly, making it especially suited for sensitivity analyses. © 2011 The Author.

Muradian R.,Radboud University Nijmegen | Muradian R.,Federal Rural University of Rio de Janeiro
Society and Natural Resources | Year: 2013

The design and thriving of payments for ecosystem services (PES) have occurred as a response to the relative failure of integrated strategies for reconciling conservation and development. The most widespread definition of PES conceives these payments as markets to solve environmental externalities. This article analyzes the limitations of this "Coasean" approach using insights from transaction costs economics, and it pleads for looking at PES with different analytical lenses. It argues that PES should be seen as "incentives for collective action." However, the extent to which incentives can contribute to the management of ES should not be taken for granted. The effects of monetary incentives are determined by their "social meanings," which are context and culture dependent. The proposed conceptual shift has significant analytical and practical implications. © 2013 Copyright Taylor and Francis Group, LLC.

Van Laerhoven H.,Emma Childrens Hospital | De Haan T.R.,Emma Childrens Hospital | Offringa M.,University of Toronto | Post B.,Radboud University Nijmegen | Van Der Lee J.H.,Emma Childrens Hospital
Pediatrics | Year: 2013

BACKGROUND AND OBJECTIVE: Hypoxic-ischemic encephalopathy (HIE) after perinatal asphyxia in term neonates causes long-term neurologic sequelae or death. A reliable evidence-based prognosis is essential. The study goal was to investigate the prognostic value of currently used clinical tests in neonatal patients with perinatal asphyxia and HIE. METHODS: Searches were made on MEDLINE, Embase, Central, and CINAHL for studies occurring between January 1980 and November 2011. Studies were included if they (1) evaluated outcome in term infants with perinatal asphyxia and HIE, (2) evaluated prognostic tests, and (3) reported outcome at a minimal follow-up age of 18 months. Study selection, assessment of methodologic quality, and data extraction were performed by 3 independent reviewers. Pooled sensitivities and specificities of investigated tests were calculated when possible. RESULTS: Of the 259 relevant studies, 29 were included describing 13 prognostic tests conducted 1631 times in 1306 term neonates. A considerable heterogeneity was noted in test performance, cut-off values, and outcome measures. The most promising tests were amplitudeintegrated electroencephalography (sensitivity 0.93, [95% confidence interval 0.78-0.98]; specificity 0.90 [0.60-0.98]), EEG (sensitivity 0.92 [0.66-0.99]; specificity 0.83 [0.64-0.93]), and visual evoked potentials (sensitivity 0.90 [0.74-0.97]; specificity 0.92 [0.68-0.98]). In imaging, diffusion weighted MRI performed best on specificity (0.89 [0.62- 0.98]) and T1/T2-weighted MRI performed best on sensitivity (0.98 [0.80-1.00]). Magnetic resonance spectroscopy demonstrated a sensitivity of 0.75 (0.26-0.96) with poor specificity (0.58 [0.23-0.87]). CONCLUSIONS: This evidence suggests an important role for amplitudeintegrated electroencephalography, EEG, visual evoked potentials, and diffusion weighted and conventional MRI. Given the heterogeneity in the tests' performance and outcomes studied, well-designed large prospective studies are needed. Copyright © 2013 by the American Academy of Pediatrics.

Rubtsov A.N.,Moscow State University | Katsnelson M.I.,Radboud University Nijmegen | Lichtenstein A.I.,University of Hamburg
Annals of Physics | Year: 2012

We develop a general theory of a boson decomposition for both local and non-local interactions in lattice fermion models which allows us to describe fermionic degrees of freedom and collective charge and spin excitations on equal footing. An efficient perturbation theory in the interaction of the fermionic and the bosonic degrees of freedom is constructed in the so-called dual variables in the path-integral formalism. This theory takes into account all local correlations of fermions and collective bosonic modes and interpolates between itinerant and localized regimes of electrons in solids. The zero-order approximation of this theory corresponds to an extended dynamical mean-field theory (EDMFT), a regular way to calculate nonlocal corrections to EDMFT is provided. It is shown that dual ladder summation gives a conserving approximation beyond EDMFT. The method is especially suitable for consideration of collective magnetic and charge excitations and allows to calculate their renormalization with respect to "bare" RPA-like characteristics. General expression for the plasmonic dispersion in correlated media is obtained. As an illustration it is shown that effective superexchange interactions in the half-filled Hubbard model can be derived within the dual-ladder approximation. © 2012 Elsevier Inc.

Itin A.P.,Radboud University Nijmegen | Itin A.P.,Russian Academy of Sciences | Katsnelson M.I.,Radboud University Nijmegen | Katsnelson M.I.,Ural Federal University
Physical Review Letters | Year: 2015

We consider 1D lattices described by Hubbard or Bose-Hubbard models, in the presence of periodic high-frequency perturbations, such as uniform ac force or modulation of hopping coefficients. Effective Hamiltonians for interacting particles are derived using an averaging method resembling classical canonical perturbation theory. As is known, a high-frequency force may renormalize hopping coefficients, causing interesting phenomena such as coherent destruction of tunneling and creation of artificial gauge fields. We find explicitly additional corrections to the effective Hamiltonians due to interactions, corresponding to nontrivial processes such as single-particle density-dependent tunneling, correlated pair hoppings, nearest neighbor interactions, etc. Some of these processes arise also in multiband lattice models, and are capable of giving rise to a rich variety of quantum phases. The apparent contradiction with other methods, e.g., Floquet-Magnus expansion, is explained. The results may be useful for designing effective Hamiltonian models in experiments with ultracold atoms, as well as in the field of ultrafast nonequilibrium magnetism. An example of manipulating exchange interaction in a Mott-Hubbard insulator is considered, where our corrections play an essential role. © 2015 American Physical Society.

Hum K.M.,University of Toronto | Manassis K.,University of Toronto | Lewis M.D.,Radboud University Nijmegen
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2013

Background: The present study was designed to examine the cortical processes that mediate cognitive regulation in response to emotion-eliciting stimuli in anxious children. Methods: Electroencephalographic (EEG) activity was recorded from clinically anxious children (n = 29) and typically developing children (n = 34). Event-related potential components were recorded while children performed a go/no-go task using facial stimuli depicting angry, calm, and happy expressions. Results: Anxious children had significantly greater posterior P1 and frontal N2 amplitudes, components associated with attention/arousal and cognitive control, respectively, than typically developing children. Anxious children also had significantly greater error-related negativities and correct-response negativities relative to typically developing children. For the anxious group only, there were no differences in neural activation between face (emotion) types or trial (Go vs. No-go) types. A regression analysis revealed that No-go N2 amplitudes for calm faces predicted self-reported anxiety levels. Conclusions: Anxious children appeared to show increased cortical activation regardless of the emotional content of the stimuli. Anxious children also showed greater medial-frontal activity regardless of task demands and response accuracy. Taken together, these findings suggest indiscriminate cortical processes that may underlie the hypervigilant regulatory style seen in clinically anxious individuals. © 2012 Association for Child and Adolescent Mental Health.

van Luijtelaar G.,Radboud University Nijmegen | Onat F.Y.,Marmara University | Gallagher M.J.,Vanderbilt University
Neurobiology of Disease | Year: 2014

While epidemiological data suggest a female prevalence in human childhood- and adolescence-onset typical absence epilepsy syndromes, the sex difference is less clear in adult-onset syndromes. In addition, although there are more females than males diagnosed with typical absence epilepsy syndromes, there is a paucity of studies on sex differences in seizure frequency and semiology in patients diagnosed with any absence epilepsy syndrome. Moreover, it is unknown if there are sex differences in the prevalence or expression of atypical absence epilepsy syndromes. Surprisingly, most studies of animal models of absence epilepsy either did not investigate sex differences, or failed to find sex-dependent effects. However, various rodent models for atypical syndromes such as the AY9944 model (prepubertal females show a higher incidence than prepubertal males), BN model (also with a higher prevalence in males) and the Gabra1 deletion mouse in the C57BL/6J strain offer unique possibilities for the investigation of the mechanisms involved in sex differences. Although the mechanistic bases for the sex differences in humans or these three models are not yet known, studies of the effects of sex hormones on seizures have offered some possibilities. The sex hormones progesterone, estradiol and testosterone exert diametrically opposite effects in genetic absence epilepsy and pharmacologically-evoked convulsive types of epilepsy models. In addition, acute pharmacological effects of progesterone on absence seizures during proestrus are opposite to those seen during pregnancy. 17β-Estradiol has anti-absence seizure effects, but it is only active in atypical absence models. It is speculated that the pro-absence action of progesterone, and perhaps also the delayed pro-absence action of testosterone, are mediated through the neurosteroid allopregnanolone and its structural and functional homolog, androstanediol. These two steroids increase extrasynaptic thalamic tonic GABAergic inhibition by selectively targeting neurosteroid-selective subunits of GABAA receptors (GABAARs). Neurosteroids also modulate the expression of GABAAR containing the γ2, α4, and δ subunits. It is hypothesized that differences in subunit expression during pregnancy and ovarian cycle contribute to the opposite effects of progesterone in these two hormonal states. © 2014 Elsevier Inc.

Wiborg J.F.,Radboud University Nijmegen | Wiborg J.F.,University of Hamburg
Psychosomatic Medicine | Year: 2013

OBJECTIVE: To examine rates of suicidality in primary care patients with somatoform disorders and to identify factors that might help to understand and manage active suicidal ideation in these patients. METHODS: We conducted a cross-sectional study screening 1645 primary care patients. In total, 142 patients fulfilled the criteria for a somatoform disorder. Suicidality and illness perceptions were assessed in these patients. RESULTS: Of the 142 patients, 23.9% had active suicidal ideation during the previous 6 months; 17.6% had attempted to commit suicide in the past, the majority after onset of the somatoform symptoms. We tested two models with suicidal ideation as a dependent variable. In the first model, comorbid symptoms of depression (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.03-1.33) and previous suicide attempts (OR= 3.02, 95% CI = 1.06-8.62) were significantly associated with suicidal ideation. Comorbid symptoms of anxiety did not yield significance. Illness perceptions and age of onset of the symptoms were then added to this model to test the role of somatoform-specific factors in addition to previous factors. In the complete model, comorbid symptoms of depression (OR = 1.15, 95% CI = 1.00-1.32) and dysfunctional illness perceptions (OR = 1.06, 95% CI = 1.01-1.11) were independently associated with active suicidal ideation, whereas the other factors did not yield significance. CONCLUSIONS: According to our data, suicidality seems to be a substantial problem in primary care patients with somatoform disorders. Dysfunctional illness perceptions may play a vital role in the understanding and management of active suicidal ideation in these patients, in addition to more established factors. Copyright © 2013 by the American Psychosomatic Society.

Rudenko A.N.,Institute of Chemical Technology | Keil F.J.,Institute of Chemical Technology | Katsnelson M.I.,Radboud University Nijmegen | Lichtenstein A.I.,University of Hamburg
Physical Review B - Condensed Matter and Materials Physics | Year: 2012

In this work, we investigate the adsorption of a single cobalt atom (Co) on graphene by means of the complete active space self-consistent field approach, additionally corrected by the second-order perturbation theory. The local structure of graphene is modeled by a planar hydrocarbon cluster (C 24H 12). Systematic treatment of the electron correlations and the possibility to study excited states allow us to reproduce the potential energy curves for different electronic configurations of Co. We find that upon approaching the surface, the ground-state configuration of Co undergoes several transitions, giving rise to two stable states. The first corresponds to the physisorption of the adatom in the high-spin 3d74s2 (S=3/2) configuration, while the second results from the chemical bonding formed by strong orbital hybridization, leading to the low-spin 3d9 (S=1/2) state. Due to the instability of the 3d9 configuration, the adsorption energy of Co is small in both cases and does not exceed 0.35 eV. We analyze the obtained results in terms of a simple model Hamiltonian that involves Coulomb repulsion (U) and exchange coupling (J) parameters for the 3d shell of Co, which we estimate from first-principles calculations. We show that while the exchange interaction remains constant upon adsorption (1.1 eV), the Coulomb repulsion significantly reduces for decreasing distances (from 5.3 to 2.6±0.2 eV). The screening of U favors higher occupations of the 3d shell and thus is largely responsible for the interconfigurational transitions of Co. Finally, we discuss the limitations of the approaches that are based on density functional theory with respect to transition metal atoms on graphene, and we conclude that a proper account of the electron correlations is crucial for the description of adsorption in such systems. © 2012 American Physical Society.

Scheenen T.W.J.,Radboud University Nijmegen | Rosenkrantz A.B.,NYU Langone Medical Center | Haider M.A.,University of Toronto | Futterer J.J.,Radboud University Nijmegen
Investigative Radiology | Year: 2015

This article reviews recent and ongoing developments in multiparametric magnetic resonance imaging (mpmri) of the prostate. Advances in T2-weighted imaging, diffusion-weighted imaging, dynamic contrast-enhanced imaging, and spectroscopic imaging are described along with advances related to radiofrequency coils and imaging at high magnetic field. As mpmri is increasingly becoming routine in various aspects of clinical prostate cancer management, its role in detection, localization, staging, assessment of aggressiveness, and active surveillance is discussed. Combined with growing clinical adoption of the techniques already at hand, continual optimization of acquisition techniques and image interpretation schemes will further strengthen the role of mpmri as an important diagnostic test in prostate cancer management. © 2015 Wolters Kluwer Health, Inc.

Sachs B.,University of Hamburg | Wehling T.O.,University of Hamburg | Katsnelson M.I.,Radboud University Nijmegen | Lichtenstein A.I.,University of Hamburg
Physical Review B - Condensed Matter and Materials Physics | Year: 2011

We investigate the adsorption of graphene sheets on h-BN substrates by means of first-principles calculations in the framework of adiabatic connection fluctuation-dissipation theory in the random-phase approximation. We obtain adhesion energies for different crystallographic stacking configurations and show that the interlayer bonding is due to long-range van der Waals forces. The interplay of elastic and adhesion energies is shown to lead to stacking disorder and moiré structures. Band-structure calculations reveal substrate induced mass terms in graphene, which change their sign with the stacking configuration. The dispersion, absolute band gaps, and the real-space shape of the low-energy electronic states in the moiré structures are discussed. We find that the absolute band gaps in the moiré structures are at least an order of magnitude smaller than the maximum local values of the mass term. Our results are in agreement with recent scanning tunneling microscopy experiments. © 2011 American Physical Society.

Wehling T.O.,University of Hamburg | Lichtenstein A.I.,University of Hamburg | Katsnelson M.I.,Radboud University Nijmegen
Physical Review B - Condensed Matter and Materials Physics | Year: 2011

We address the interaction of graphene with 3d transition-metal adatoms and the formation of localized magnetic moments by means of first-principles calculations. By comparing calculations within the generalized gradient approximation (GGA) to GGA + U we find that the electronic configuration and the adsorption geometries can be very sensitive to effects of local Coulomb interactions U in the transition-metal d orbitals. We find high-spin configurations being favorable for Cr and Mn adatoms independent of the functional. For Fe, Co, and Ni different electronic configurations are realized depending on the value of the local Coulomb interaction strength U. Chemical control over the spin of the adatoms by hydrogenation is demonstrated: NiH and CoH adsorbed to graphene exhibit spin S=1/2 and S=1, respectively. © 2011 American Physical Society.

Gemmeke J.F.,Radboud University Nijmegen | Virtanen T.,Tampere University of Technology | Hurmalainen A.,Tampere University of Technology
IEEE Transactions on Audio, Speech and Language Processing | Year: 2011

This paper proposes to use exemplar-based sparse representations for noise robust automatic speech recognition. First, we describe how speech can be modeled as a linear combination of a small number of exemplars from a large speech exemplar dictionary. The exemplars are time-frequency patches of real speech, each spanning multiple time frames. We then propose to model speech corrupted by additive noise as a linear combination of noise and speech exemplars, and we derive an algorithm for recovering this sparse linear combination of exemplars from the observed noisy speech. We describe how the framework can be used for doing hybrid exemplar-based/HMM recognition by using the exemplar-activations together with the phonetic information associated with the exemplars. As an alternative to hybrid recognition, the framework also allows us to take a source separation approach which enables exemplar-based feature enhancement as well as missing data mask estimation. We evaluate the performance of these exemplar-based methods in connected digit recognition on the AURORA-2 database. Our results show that the hybrid system performed substantially better than source separation or missing data mask estimation at lower signal-to-noise ratios (SNRs), achieving up to 57.1% accuracy at SNR=- 5 db. Although not as effective as two baseline recognizers at higher SNRs, the novel approach offers a promising direction of future research on exemplar-based ASR. © 2006 IEEE.

Blanken M.O.,University Utrecht | Rovers M.M.,University Utrecht | Rovers M.M.,Radboud University Nijmegen | Molenaar J.M.,University Utrecht | And 4 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: Respiratory syncytial virus (RSV) infection is associated with subsequent recurrent wheeze. Observational studies cannot determine whether RSV infection is the cause of recurrent wheeze or the first indication of preexistent pulmonary vulnerability in preterm infants. The monoclonal antibody palivizumab has shown efficacy in preventing severe RSV infection in high-risk infants. METHODS: In the double-blind, placebo-controlled MAKI trial, we randomly assigned 429 otherwise healthy preterm infants born at a gestational age of 33 to 35 weeks to receive either monthly palivizumab injections (214 infants) or placebo (215 infants) during the RSV season. The prespecified primary outcome was the total number of parent-reported wheezing days in the first year of life. Nasopharyngeal swabs were taken during respiratory episodes for viral analysis. RESULTS: Palivizumab treatment resulted in a relative reduction of 61% (95% confidence interval, 56 to 65) in the total number of wheezing days during the first year of life (930 of 53,075 days in the RSV-prevention group [1.8%] vs. 2309 of 51,726 days [4.5%] in the placebo group). During this time, the proportion of infants with recurrent wheeze was 10 percentage points lower in patients treated with palivizumab (11% vs. 21%, P = 0.01). CONCLUSIONS: In otherwise healthy preterm infants, palivizumab treatment resulted in a significant reduction in wheezing days during the first year of life, even after the end of treatment. These findings implicate RSV infection as an important mechanism of recurrent wheeze during the first year of life in such infants. (Funded by Abbott Laboratories and by the Netherlands Organization for Health Research and Development; MAKI Controlled Clinical Trials number, ISRCTN73641710.) Copyright © 2013 Massachusetts Medical Society.

Wang A.,Radboud University Nijmegen | Cui Y.,CAS Institute of Chemistry | Li J.,CAS Institute of Chemistry | Van Hest J.C.M.,Radboud University Nijmegen
Advanced Functional Materials | Year: 2012

In this paper, we propose a "casting" strategy to prepare intrinsically fluorescent, uniform and porous gelatin microgels with multi-responsiveness. Gelatin microgels with tunable size were obtained by copying the structure of a porous CaCO 3 template. The diameter of the gelatin microgels was sensitive to salt concentration and pH. Doxorubicin and Rhodamine B as model drugs were loaded into the microgels via electrostatic interaction and release of the payload was triggered by changing the salt concentration and pH, respectively. Cell experiments demonstrated that the gelatin microgels had an excellent biocompatibility and biodegradability. The merits of gelatin microgels such as tunable size, biocompatibility, and stimulus responsive upload and release of positively charged small molecules will permit the microgels as excellent carriers for drug delivery. The whole manufacturing process is furthermore environmental-friendly involving no organic solvents and surfactants. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Tretmans J.,Embedded Systems Institute | Tretmans J.,Radboud University Nijmegen
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2011

Model-based testing is one of the promising technologies to increase the efficiency and effectiveness of software testing. In model-based testing, a model specifies the required behaviour of a system, and test cases are algorithmically generated from this model. Obtaining a valid model, however, is often difficult if the system is complex, contains legacy or third-party components, or if documentation is incomplete. Test-based modelling, also called automata learning, turns model-based testing around: it aims at automatically generating a model from test observations. This paper first gives an overview of formal, model-based testing in general, and of model-based testing for labelled transition system models in particular. Then the practice of model-based testing, the difficulty of obtaining models, and the role of learning are discussed. It is shown that model-based testing and learning are strongly related, and that learning can be fully expressed in the concepts of model-based testing. In particular, test coverage in model-based testing and precision of learned models turn out to be two sides of the same coin. © 2011 Springer-Verlag.

Low T.,IBM | Low T.,Purdue University | Guinea F.,CSIC - Institute of Materials Science | Katsnelson M.I.,Radboud University Nijmegen
Physical Review B - Condensed Matter and Materials Physics | Year: 2011

We show that when the pseudomagnetic fields created by long-wavelength deformations are appropriately coupled with a scalar electric potential, a significant energy gap can emerge due to the formation of a Haldane state. Ramifications of this physical effect are examined through the study of various strain geometries commonly seen in experiments, such as strain superlattices and wrinkled suspended graphene. Of particular technological importance, we consider setups where this gap can be tunable through electrostatic gates, allowing for the design of electronic devices not realizable with other materials. © 2011 American Physical Society.

Dinarello C.A.,Aurora University | Dinarello C.A.,Radboud University Nijmegen
Blood | Year: 2011

More than any other cytokine family, the IL-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. The cytosolic segment of each IL-1 receptor family member contains the Toll-IL-1-receptor domain. This domain is also present in each Tolllike receptor, the receptors that respond to microbial products and viruses. Since Toll-IL-1-receptor domains are functional for both receptor families, responses to the IL-1 family are fundamental to innate immunity. Of the 11 members of the IL-1 family, IL-1β has emerged as a therapeutic target for an expanding number of systemic and local inflammatory conditions called autoinflammatory diseases. For these, neutralization of IL-1β results in a rapid and sustained reduction in disease severity. Treatment for autoimmune diseases often includes immunosuppressive drugs whereas neutralization of IL-1β is mostly anti-inflammatory. Although some autoinflammatory diseases are due to gain-of-function mutations for caspase-1 activity, common diseases such as gout, type 2 diabetes, heart failure, recurrent pericarditis, rheumatoid arthritis, and smoldering myeloma also are responsive to IL-1β neutralization. This review summarizes acute and chronic inflammatory diseases that are treated by reducing IL-1β activity and proposes that disease severity is affected by the anti-inflammatory members of the IL-1 family of ligands and receptors.

Alexander S.,University of Würzburg | Alexander S.,University of Houston | Friedl P.,University of Würzburg | Friedl P.,University of Houston | Friedl P.,Radboud University Nijmegen
Trends in Molecular Medicine | Year: 2012

Cancer progression and outcome depend upon two key functions executed by tumor cells: the growth and survival capability leading to resistance to therapy and the invasion into host tissues resulting in local and metastatic dissemination. Although both processes are widely studied separately, the underlying cell-intrinsic and microenvironmentally controlled signaling pathways reveal substantial overlap in mechanism. Candidate signaling hubs that serve both tumor invasion and resistance include growth factor and chemokine signaling, integrin engagement, and components of the Ras/MAPKs, PI3K, and mTOR signaling pathways. In this review, we summarize these and other mechanisms controlled by the microenvironment that jointly support cancer cell survival and resistance, as well as the invasion machinery. We also discuss their interdependencies and the implications for therapeutic dual- or multi-pathway targeting. © 2011 Elsevier Ltd.

Hagenaars M.A.,Health and Neuropsychology | van Minnen A.,GGZ Nijmegen | Hoogduin K.A.L.,Radboud University Nijmegen
Behaviour Research and Therapy | Year: 2010

This study investigates the impact of dissociative phenomena and depression on the efficacy of prolonged exposure treatment in 71 patients with posttraumatic stress disorder (PTSD). Diagnoses, comorbidity, pretreatment depressive symptoms, PTSD symptom severity, and dissociative phenomena (trait dissociation, numbing, and depersonalization) were assessed at pretreatment using semi-structured interviews and questionnaires. In a pretreatment behavioral exposure test, patients were imaginally exposed to (part of) their trauma memory for 9 min, during which subjective fear was assessed. At posttreatment and 6 months follow-up PTSD, depressive and dissociative symptoms were again assessed in the completers (n = 60). Pretreatment levels of dissociative and depressive symptoms were similar in dropouts and completers and none of the dissociative phenomena nor depression predicted improvement. Against expectations, dissociative phenomena and depression were associated with enhanced rather than impeded fear activation during the behavioral exposure test. However, these effects disappeared after controlling for initial PTSD severity. Hence, rather than supporting contraindication, the current results imply that patients presenting with even severe dissociative or depressive symptoms may profit similarly from exposure treatment as do patients with minimal dissociative or depressive symptoms. © 2009 Elsevier Ltd. All rights reserved.

Dinarello C.A.,Aurora University | Dinarello C.A.,Radboud University Nijmegen
Cell | Year: 2010

Inflammation involving the innate and adaptive immune systems is a normal response to infection. However, when allowed to continue unchecked, inflammation may result in autoimmune or autoinflammatory disorders, neurodegenerative disease, or cancer. A variety of safe and effective anti-inflammatory agents are available, including aspirin and other nonsteroidal anti-inflammatories, with many more drugs under development. In particular, the new era of anti-inflammatory agents includes " biologicals" such as anticytokine therapies and small molecules that block the activity of kinases. Other anti-inflammatories currently in use or under development include statins, histone deacetylase inhibitors, PPAR agonists, and small RNAs. This Review discusses the current status of anti-inflammatory drug research and the development of new anti-inflammatory therapeutics. © 2010 Elsevier Inc.

Dinarello C.A.,Aurora University | Dinarello C.A.,Radboud University Nijmegen
Cancer and Metastasis Reviews | Year: 2010

The clinical successes of targeting angiogenesis provide a basis for trials of interleukin-1 (IL-1) blockade and particularly anti-IL-1β as an add-on therapy in human metastatic disease. In animal studies for over 20 years, IL-1 has been demonstrated to increase adherence of tumor cells to the endothelium in vitro, and administration of IL-1 to mice increases the number of metastatic colonies and tumor growth. Importantly, reducing endogenous IL-1 activity, particularly IL-1β, with the naturally occurring IL-1 receptor antagonist (IL-1Ra) reduces both metastasis as well as tumor burden. Inhibition of IL-1 activity prevents in vivo blood vessel formation induced by products released from hypoxic macrophages or vascular endothelial cell growth factor itself. Mice deficient in IL-1β do not form blood vessels in matrigels embedded with vascular endothelial cell growth factor or containing products of macrophages. Recombinant IL-1Ra (anakinra) has been administered to over 1,000 patients with septic shock resulting in a consistent reduction in all-cause 28-day mortality. Approved for treatment of rheumatoid arthritis, anakinra has a remarkable safety record. Anakinra resulted in decreased blood vessels in the pannus of affected joints in patients with rheumatoid arthritis. Neutralizing monoclonal antibodies to IL-1β and a soluble receptor to IL-1 are approved for treating chronic inflammatory diseases. Given the availability of three therapeutic agents for limiting IL-1 activity, the safety of blocking IL-1, and the clear benefit of blocking IL-1 activity in animal models of metastasis and angiogenesis, clinical trials of IL-1 blockade should be initiated, particularly as an add-on therapy of patients receiving antiangiogenesis-based therapies. © The Author(s) 2010.

Friedl P.,Radboud University Nijmegen | Wolf K.,University of Houston | Zegers M.M.,Radboud University Nijmegen
Nature Cell Biology | Year: 2014

Collective cell migration depends on multicellular mechanocoupling between leader and follower cells to coordinate traction force and position change. Co-registration of Rho GTPase activity and forces in migrating epithelial cell sheets now shows how RhoA controls leader-follower cell hierarchy, multicellular cytoskeletal contractility and mechanocoupling, to prevent ectopic leading edges and to move the cell sheet forward. © 2014 Macmillan Publishers Limited. All rights reserved.

Wolf K.,Radboud University Nijmegen | Friedl P.,Radboud University Nijmegen | Friedl P.,University of Houston
Trends in Cell Biology | Year: 2011

Cell invasion into the 3D extracellular matrix (ECM) is a multistep biophysical process involved in inflammation, tissue repair, and metastatic cancer invasion. Migrating cells navigate through tissue structures of complex and often varying physicochemical properties, including molecular composition, porosity, alignment and stiffness, by adopting strategies that involve deformation of the cell and engagement of matrix-degrading proteases. We review how the ECM determines whether or not pericellular proteolysis is required for cell migration, ranging from protease-driven invasion and secondary tissue destruction, to non-proteolytic, non-destructive movement that solely depends on cell deformability and available tissue space. These concepts call for therapeutic targeting of proteases to prevent invasion-associated tissue destruction rather than the migration process per se. © 2011 Elsevier Ltd.

Friedl P.,Radboud University Nijmegen | Friedl P.,University of Houston | Friedl P.,University of Würzburg | Alexander S.,University of Houston | Alexander S.,University of Würzburg
Cell | Year: 2011

Cancer invasion is a cell-and tissue-driven process for which the physical, cellular, and molecular determinants adapt and react throughout the progression of the disease. Cancer invasion is initiated and maintained by signaling pathways that control cytoskeletal dynamics in tumor cells and the turnover of cell-matrix and cell-cell junctions, followed by cell migration into the adjacent tissue. Here, we describe the cell-matrix and cell-cell adhesion, protease, and cytokine systems that underlie tissue invasion by cancer cells. We explain how the reciprocal reprogramming of both the tumor cells and the surrounding tissue structures not only guides invasion, but also generates diverse modes of dissemination. The resulting "plasticity" contributes to the generation of diverse cancer invasion routes and programs, enhanced tumor heterogeneity, and ultimately sustained metastatic dissemination. © 2011 Elsevier Inc.

Codello A.,International School for Advanced Studies | Demmel M.,University of Mainz | Zanusso O.,Radboud University Nijmegen
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2014

We prove that the functional renormalization group flow equation admits a perturbative solution and show explicitly the scheme transformation that relates it to the standard schemes of perturbation theory. We then define a universal scheme within the functional renormalization group. © 2014 American Physical Society.

Videnovic A.,Massachusetts General Hospital | Lazar A.S.,University of Cambridge | Barker R.A.,University of Cambridge | Overeem S.,Radboud University Nijmegen
Nature Reviews Neurology | Year: 2014

Circadian rhythms are physiological and behavioural cycles generated by an endogenous biological clock, the suprachiasmatic nucleus. The circadian system influences the majority of physiological processes, including sleep-wake homeostasis. Impaired sleep and alertness are common symptoms of neurodegenerative disorders, and circadian dysfunction might exacerbate the disease process. The pathophysiology of sleep-wake disturbances in these disorders remains largely unknown, and is presumably multifactorial. Circadian rhythm dysfunction is often observed in patients with Alzheimer disease, in whom it has a major impact on quality of life and represents one of the most important factors leading to institutionalization of patients. Similarly, sleep and circadian problems represent common nonmotor features of Parkinson disease and Huntington disease. Clinical studies and experiments in animal models of neurodegenerative disorders have revealed the progressive nature of circadian dysfunction throughout the course of neurodegeneration, and suggest strategies for the restoration of circadian rhythmicity involving behavioural and pharmacological interventions that target the sleep-wake cycle. In this Review, we discuss the role of the circadian system in the regulation of the sleep-wake cycle, and outline the implications of disrupted circadian timekeeping in neurodegenerative diseases. © 2014 Macmillan Publishers Limited. All rights reserved.

Dinarello C.A.,Aurora University | Dinarello C.A.,Radboud University Nijmegen
European Journal of Immunology | Year: 2011

An expanding spectrum of acute and chronic non-infectious inflammatory diseases is uniquely responsive to IL-1β neutralization. IL-1β-mediated diseases are often called "auto-inflammatory" and the dominant finding is the release of the active form of IL-1β driven by endogenous molecules acting on the monocyte/macrophage. IL-1β activity is tightly controlled and requires the conversion of the primary transcript, the inactive IL-1β precursor, to the active cytokine by limited proteolysis. Limited proteolysis can take place extracellularly by serine proteases, released in particular by infiltrating neutrophils or intracellularly by the cysteine protease caspase-1. Therefore, blocking IL-1β resolves inflammation regardless of how the cytokine is released from the cell or how the precursor is cleaved. Endogenous stimulants such as oxidized fatty acids and lipoproteins, high glucose concentrations, uric acid crystals, activated complement, contents of necrotic cells, and cytokines, particularly IL-1 itself, induce the synthesis of the inactive IL-1β precursor, which awaits processing to the active form. Although bursts of IL-1β precipitate acute attacks of systemic or local inflammation, IL-1β also contributes to several chronic diseases. For example, ischemic injury, such as myocardial infarction or stroke, causes acute and extensive damage, and slowly progressive inflammatory processes take place in atherosclerosis, type 2 diabetes, osteoarthritis and smoldering myeloma. Evidence for the involvement of IL-1β and the clinical results of reducing IL-1β activity in this broad spectrum of inflammatory diseases are the focus of this review. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Gritsenko P.G.,Radboud University Nijmegen | Ilina O.,Radboud University Nijmegen | Friedl P.,Radboud University Nijmegen | Friedl P.,University of Houston
Journal of Pathology | Year: 2012

Cancer cell invasion into healthy tissues develops preferentially along pre-existing tracks of least resistance, followed by secondary tissue remodelling and destruction. The tissue scaffolds supporting or preventing guidance of invasion vary in structure and molecular composition between organs. In the brain, the guidance is provided by myelinated axons, astrocyte processes, and blood vessels which are used as invasion routes by glioma cells. In the human breast, containing interstitial collagen-rich connective tissue, disseminating breast cancer cells preferentially invade along bundled collagen fibrils and the surface of adipocytes. In both invasion types, physical guidance prompted by interfaces and space is complemented by molecular guidance. Generic mechanisms shared by most, if not all, tissues include (i) guidance by integrins towards fibrillar interstitial collagen and/or laminins and type IV collagen in basement membranes decorating vessels and adipocytes, and, likely, CD44 engaging with hyaluronan; (ii) haptotactic guidance by chemokines and growth factors; and likely (iii) physical pushing mechanisms. Tissue-specific, resticted guidance cues include ECM proteins with restricted expression (tenascins, lecticans), cell-cell interfaces, and newly secreted matrix molecules decorating ECM fibres (laminin-332, thrombospondin-1, osteopontin, periostin). We here review physical and molecular guidance mechanisms in interstitial tissue and brain parenchyma and explore shared principles and organ-specific differences, and their implications for experimental model design and therapeutic targeting of tumour cell invasion. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Gemmeke J.F.,Radboud University Nijmegen | Virtanen T.,Tampere University of Technology
ICASSP, IEEE International Conference on Acoustics, Speech and Signal Processing - Proceedings | Year: 2010

This paper proposes a noise robust exemplar-based speech recognition system where noisy speech is modeled as a linear combination of a set of speech and noise exemplars. The method works by finding a small number of labeled exemplars in a very large collection of speech and noise exemplars that jointly approximate the observed speech signal. We represent the exemplars using melenergies, which allows modeling the summation of speech and noise, and estimate the activations of the exemplars by minimizing the generalized Kullback-Leibler divergence between the observations and the model. The activations of the speech exemplars are directly being used for recognition. This approach proves to be promising, achieving up to 55.8% accuracy at signal-to-noise ratio -5 dB on the AURORA-2 connected digit recognition task. ©2010 IEEE.

Parker B.C.,University of Houston | Engels M.,University of Houston | Engels M.,Radboud University Nijmegen | Annala M.,Tampere University of Technology | Zhang W.,University of Houston
Journal of Pathology | Year: 2014

The emergence of fibroblast growth factor receptor (FGFR) family fusions across diverse cancers has brought attention to FGFR-derived cancer therapies. The discovery of the first recurrent FGFR fusion in glioblastoma was followed by discoveries of FGFR fusions in bladder, lung, breast, thyroid, oral, and prostate cancers. Drug targeting of FGFR fusions has shown promising results and should soon be translating into clinical trials. FGFR fusions form as a result of various mechanisms - predominantly deletion for FGFR1, translocation for FGFR2, and tandem duplication for FGFR3. The ability to exploit the unique targetability of FGFR fusions proves that FGFR-derived therapies could have a promising future in cancer therapeutics. Drug targeting of fusion genes has proven to be an extremely effective therapeutic approach for cancers such as the recurrent BCR-ABL1 fusion in chronic myeloid leukaemia. The recent discovery of recurrent FGFR family fusions in several cancer types has brought to attention the unique therapeutic potential for FGFR-positive patients. Understanding the diverse mechanisms of FGFR fusion formation and their oncogenic potential will shed light on the impact of FGFR-derived therapy in the future. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Scharenborg O.,Radboud University Nijmegen
Journal of the Acoustical Society of America | Year: 2010

Evidence that listeners, at least in a laboratory environment, use durational cues to help resolve temporarily ambiguous speech input has accumulated over the past decades. This paper introduces Fine-Tracker, a computational model of word recognition specifically designed for "tracking" fine-phonetic information in the acoustic speech signal and using it during word recognition. Two simulations were carried out using real speech as input to the model. The simulations showed that the Fine-Tracker, as has been found for humans, benefits from durational information during word recognition, and uses it to disambiguate the incoming speech signal. The availability of durational information allows the computational model to distinguish embedded words from their matrix words (first simulation), and to distinguish word final realizations of [s] from word initial realizations (second simulation). Fine-Tracker thus provides the first computational model of human word recognition that is able to extract durational information from the speech signal and to use it to differentiate words. © 2010 Acoustical Society of America.

Wanten G.J.A.,Radboud University Nijmegen
Best Practice and Research: Clinical Gastroenterology | Year: 2016

Severe malabsorption of fluids and nutrients leads to intestinal failure (IF) where intravenous supplementation of nutrients and fluids is necessary to maintain health and/or growth. Long-term treatment of IF implies the start of intravenous support in the outpatient setting (home parenteral nutrition, HPN). Although HPN has proven lifesaving for many patients for more than four decades this strategy remains associated with complications that compromise the quality of life. Many problems relate to the presence of the venous access device and concern infections or vascular occlusion due to thrombosis. Patient training remains key to prevent these complications. Also metabolic problems may arise that involve liver function or composition or bone mineralization. While intestinal transplantation remains inferior to HPN as alternative treatment strategy in terms of survival, promising developments include the introduction of hormones that promote intestinal adaptation, mixed lipid emulsions that decrease liver problems and catheter lock solutions that prevent infections. © 2016 Elsevier Ltd. All rights reserved.

Jin Y.,Radboud University Nijmegen | Cristescu S.M.,Radboud University Nijmegen | Harren F.J.M.,Radboud University Nijmegen | Mandon J.,Radboud University Nijmegen
Optics Letters | Year: 2014

We present a femtosecond optical parametric oscillator (OPO) containing two magnesium-doped periodically poled lithium niobate crystals in a singly resonant ring cavity, pumped by two mode-locked Yb-fiber lasers. As such, the OPO generates two idler combs (up to 220 mW), covering a wavelength range from 2.7 to 4.2 μm, from which a midinfrared dual-comb Fourier transform spectrometer is constructed. By detecting the heterodyning signal between the two idler beams a full broadband spectrum of a molecular gas can be observed over 250 cm?1 within 70 μs with a spectral resolution of 15 GHz. The absorption and dispersion spectra of acetylene and methane have been measured round 3000 cm?1, indicating that this OPO represents an ideal broadband mid-infrared source for fast chemical sensing. © 2014 Optical Society of America.

Snaphaan L.,Radboud University Nijmegen | van der Werf S.,Radboud University Nijmegen | de Leeuw F.-E.,Radboud University Nijmegen
European Journal of Neurology | Year: 2011

Background: Post-stroke fatigue (PSF) often occurs after stroke and has a negative impact on the rehabilitation process. Several studies focused either on short- or on long-term PSF and their relations with stroke characteristics. However, possible pre-stroke risk factors such as history of depression, pre-existent white matter lesions or brain atrophy were usually not taken into account. Therefore, the precise mechanisms underlying PSF remain still unclear. This study was aimed at assessing the possible contributions of (pre-)stroke factors to both short-term PSF and its course over time. Methods: This study pertains to 108 patients with an acute cerebral infarction. PSF was rated by the Checklist Individual Strength at 2months and 1.5year post-stroke. The relation between (pre-)stroke factors and PSF was assessed with multivariate regression analysis. Results: The prevalence of baseline PSF was 35% and at follow-up 33%. Older age had a protective effect on PSF at baseline (OR 0.95; 95% CI 0.91-0.98), whereas post-stroke depressive symptoms and infratentorial infarctions were related to an increased risk for PSF (OR 1.40; 95% CI 1.21-1.63 and OR 4.69; 95% CI 1.03-21.47, respectively). Baseline fatigue was related to an increased risk of PSF at follow-up (OR 1.15; 95% CI 1.09-1.22). Conclusions: Predictors for baseline fatigue were younger age, post-stroke depressive symptoms, and infratentorial infarctions. Baseline fatigue did predict fatigue outcome over time, suggesting that early interventions might be useful to prevent deteriorated PSF. © 2010 The Author(s). European Journal of Neurology © 2010 EFNS.

Netea M.G.,Radboud University Nijmegen | Quintin J.,Radboud University Nijmegen | Van Der Meer J.W.M.,Radboud University Nijmegen
Cell Host and Microbe | Year: 2011

Immune responses in vertebrates are classically divided into innate and adaptive, with only the latter being able to build up immunological memory. However, although lacking adaptive immune responses, plants and invertebrates are protected against reinfection with pathogens, and invertebrates even display transplant rejection. In mammals, past "forgotten" studies demonstrate cross-protection between infections independently of T and B cells, and more recently memory properties for NK cells and macrophages, prototypical cells of innate immunity, have been described. We now posit that mammalian innate immunity also exhibits an immunological memory of past insults, for which we propose the term "trained immunity." Understanding trained immunity will revolutionize our view of host defense and immunological memory, and could lead to defining a new class of vaccines and immunotherapies. © 2011 Elsevier Inc.

Maoz D.,Tel Aviv University | Mannucci F.,National institute for astrophysics | Nelemans G.,Radboud University Nijmegen | Nelemans G.,Catholic University of Leuven
Annual Review of Astronomy and Astrophysics | Year: 2014

Type Ia supernovae (SNe Ia) are important distance indicators, element factories, cosmic-ray accelerators, kinetic-energy sources in galaxy evolution, and end points of stellar binary evolution. It has long been clear that a SN Ia must be the runaway thermonuclear explosion of a degenerate carbon-oxygen stellar core, most likely a white dwarf (WD). However, the specific progenitor systems of SNe Ia, and the processes that lead to their ignition, have not been identified. Two broad classes of progenitor binary systems have long been considered: single-degenerate (SD), in which a WD gains mass from a nondegenerate star; and double-degenerate (DD), involving the merger of two WDs. New theoretical work has enriched these possibilities with some interesting updates and variants. We review the significant recent observational progress in addressing the progenitor problem. We consider clues that have emerged from the observed properties of the various proposed progenitor populations, from studies of SN Ia sites pre- and postexplosion from analysis of the explosions themselves and from the measurement of event rates. The recent nearby and well-studied event, SN 2011fe, has been particularly revealing. The observational results are not yet conclusive and sometimes prone to competing theoretical interpretations. Nevertheless, it appears that DD progenitors, long considered the underdog option, could be behind some, if not all, SNe Ia. We point to some directions that may lead to future progress. Copyright © 2014 by Annual Reviews.

Frencken J.E.,Radboud University Nijmegen
Dental Materials | Year: 2010

Dental caries is the most prevalent non-communicable disease in the world. Its management in high-income countries over the last four decades has resulted in relatively low caries prevalence in child and adolescent populations. In low- and middle-income countries, caries management is virtually non-existent and this may lead to serious physical and mental complications, particularly in children. Toothache is predominantly treated by extracting the cavitated tooth. Absence of restorative oral care is partly due to the copying from high-income countries, of restorative treatment reliant on electrically driven equipment and often inappropriate for use in many low- and middle-income countries. Atraumatic Restorative Treatment (ART), which does not rely on electrically driven equipment, has yielded good results over the last two decades. ART uses hand instruments and high-viscosity glass-ionomers. Its introduction into public oral healthcare systems has been piloted in several countries. Initial short-term results show that the introduction of ART, using high-viscosity glass-ionomers, has increased the ratio of restorations to extractions. Moreover, the percentage of ART restorations in relation to the total number of restorations placed increased steeply after its introduction and has remained high. However, ART introduction faced a few barriers, the most important being high patient workloads and the absence of a constant supply of dental instruments and glass-ionomers. High-viscosity glass-ionomer has become an essential element in public oral healthcare systems, particularly in those operating inadequately. © 2009 Academy of Dental Materials.

Cho K.,Radboud University Nijmegen
Electronic Proceedings in Theoretical Computer Science, EPTCS | Year: 2014

This paper presents a novel semantics for a quantum programming language by operator algebras, which are known to give a formulation for quantum theory that is alternative to the one by Hilbert spaces. We show that the opposite category of the category of W∗-algebras and normal completely positive subunital maps is an elementary quantum flow chart category in the sense of Selinger. As a consequence, it gives a denotational semantics for Selinger's first-order functional quantum programming language QPL. The use of operator algebras allows us to accommodate infinite structures and to handle classical and quantum computations in a unified way. © K. Cho.

Adams R.,Radboud University Nijmegen
Electronic Proceedings in Theoretical Computer Science, EPTCS | Year: 2014

We present the syntax and rules of deduction of QPEL (Quantum Program and Effect Language), a language for describing both quantum programs, and properties of quantum programs - effects on the appropriate Hilbert space. We show how semantics may be given in terms of state-and-effect triangles, a categorical setting that allows semantics in terms of Hilbert spaces, C∗-algebras, and other categories. We prove soundness and completeness results that show the derivable judgements are exactly those provable in all state-and-effect triangles.

Cseke B.,Radboud University Nijmegen | Heskes T.,Radboud University Nijmegen
Journal of Machine Learning Research | Year: 2011

We consider the problem of improving the Gaussian approximate posterior marginals computed by expectation propagation and the Laplace method in latent Gaussian models and propose methods that are similar in spirit to the Laplace approximation of Tierney and Kadane (1986). We show that in the case of sparse Gaussian models, the computational complexity of expectation propagation can be made comparable to that of the Laplace method by using a parallel updating scheme. In some cases, expectation propagation gives excellent estimates where the Laplace approximation fails. Inspired by bounds on the correct marginals, we arrive at factorized approximations, which can be applied on top of both expectation propagation and the Laplace method. The factorized approximations can give nearly indistinguishable results from the non-factorized approximations and their computational complexity scales linearly with the number of variables. We experienced that the expectation propagation based marginal approximations we introduce are typically more accurate than the methods of similar complexity proposed by Rue et al. (2009). © 2011 Botond Cseke and Tom Heskes.

Van Geffen M.,Radboud University Nijmegen | Van Heerde W.L.,Radboud University Nijmegen
Thrombosis Research | Year: 2012

Bleeding and thrombosis are the ultimate clinical outcomes of aberrations in the haemostatic process. Haemostasis prevents excessive blood loss due to the effort of various compartments like the vasculature, blood cells, coagulation and fibrinolysis. The complexity of all processes involved makes the diagnosis of aberrations difficult, cumbersome and expensive. A single assay to detect any factor disturbing this haemostatic balance with high sensitivity and specificity would be of great value, especially if the outcome of this assay correlates well with clinical outcome. Despite years of research, such an assay is not yet available; however, some interesting candidates are under development and combine the effects of various compartments. This review describes the development of global haemostasis assays and summarizes the current state of the art of these haemostasis assays covering thrombin and plasmin generation, turbidity and thromboelastography/thromboelastometry. Finally, we discuss the applicability of global assays in clinical practice and we provide a future perspective on the ongoing development of automation and miniaturisation as it is our belief that these developments will benefit the standardization of global haemostasis assays. © 2011 Elsevier Ltd. All rights reserved.

Sowa M.,Radboud University Nijmegen | Meulenbroek R.,Radboud University Nijmegen
Research in Autism Spectrum Disorders | Year: 2012

It is generally agreed that regular physical exercise promotes physical and mental health, but what are the benefits in people with Autism Spectrum Disorders (ASD)? This meta-analysis evaluates 16 behavioural studies reporting on a total of 133 children and adults with various variants of the syndrome who were offered structured physical activities either in an individual or a group context. The effects on social and motor deficiencies, two of the three primary symptom clusters of ASD, were normalized to afford a quantitative evaluation. Results pertaining to communication deficits were insufficient to permit classification. All activity programmes yielded significant progress on the measures assessed, but the individual programmes elicited significantly more improvement than the group interventions in the motor and, more surprisingly, also in the social domain. Although overall sample sizes were small, the combined results do permit the tentative conclusion that in terms of motor performance and social skills children and adults with ASD benefit most from individual exercise interventions. Further research of the impact of individual and group interventions on communication deficits in particular as well as studies gauging the extent to which exercise effects depend on ASD symptom severity are warranted. © 2011 Elsevier Ltd.

van de Veerdonk F.L.,Radboud University Nijmegen | Kullberg B.-J.,Radboud University Nijmegen | Netea M.G.,Radboud University Nijmegen
Clinical Microbiology and Infection | Year: 2012

Despite the discovery in the last decade of azoles and echinocandins as novel and potent antimycotic drugs, systemic Candida infections are still accompanied by an unacceptably high burden of morbidity and mortality. A rational novel therapeutic approach would be the use of adjuvant immunotherapy, with the aim of improving host defence against Candida. Increases in our understanding of the mechanisms that underlie the pathogenesis of Candida infections, such as the role played by pattern recognition receptors and the induction of proinflammatory cytokines during the early phases of infection, have led to the hypothesis of a potential therapeutic role of recombinant cytokines in systemic candidiasis. In the present review, we give an update of both experimental data and proof-of-principle studies in humans that argue for the use of adjunctive immunotherapy with recombinant cytokines in invasive Candida infections. Sufficiently powered studies on the role of cytokine-based treatment regimens for invasive candidiasis are needed to fully demonstrate the feasibility of this immunotherapeutic approach to improve the prognosis of severe invasive Candida infections. © 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.

Canalle L.A.,Radboud University Nijmegen | Lowik D.W.P.M.,Radboud University Nijmegen | Van Hest J.C.M.,Radboud University Nijmegen
Chemical Society Reviews | Year: 2010

Creating bioconjugates by combining polymers with peptides and proteins is an emerging multidisciplinary field of research that has enjoyed increased attention within the scientific community. This critical review provides an overview of the strategies employed for the construction of these materials and will highlight the underlying synthetic methods used. This review is therefore relevant for chemists, material scientists and chemical biologists facing the challenge of constructing polypeptide-polymer bioconjugates in a controlled fashion (269 references). © 2010 The Royal Society of Chemistry.

Simmer F.,Radboud University Nijmegen
Epigenetics : official journal of the DNA Methylation Society | Year: 2012

Aberrant DNA methylation often occurs in colorectal cancer (CRC). In our study we applied a genome-wide DNA methylation analysis approach, MethylCap-seq, to map the differentially methylated regions (DMRs) in 24 tumors and matched normal colon samples. In total, 2687 frequently hypermethylated and 468 frequently hypomethylated regions were identified, which include potential biomarkers for CRC diagnosis. Hypermethylation in the tumor samples was enriched at CpG islands and gene promoters, while hypomethylation was distributed throughout the genome. Using epigenetic data from human embryonic stem cells, we show that frequently hypermethylated regions coincide with bivalent loci in human embryonic stem cells. DNA methylation is commonly thought to lead to gene silencing; however, integration of publically available gene expression data indicates that 75% of the frequently hypermethylated genes were most likely already lowly or not expressed in normal tissue. Collectively, our study provides genome-wide DNA methylation maps of CRC, comprehensive lists of DMRs, and gives insights into the role of aberrant DNA methylation in CRC formation.

Stalmeier P.F.M.,Radboud University Nijmegen
Medical Decision Making | Year: 2011

Background. Patient adherence to medication or lifestyle interventions is a serious concern. Interventions to improve adherence exist, but their effects are usually small. Several authors suggested that decision aids may positively affect adherence. Objective. This presentation examines the role of decision aids in adherence research through development of a model and a narrative review. Methods and Results. I: A model was developed to organize pathways relating decision aids and adherence. There is clinical evidence for these pathways, suggesting that decision aids may potentially improve adherence. The model is helpful when considering measures to study decision aids and adherence. II: A narrative review of decision aids and adherence was done. A systematic search resulted in 11 randomized studies. Two studies, both in the hypertension management domain, were positive. Shortcomings were identified regarding the range of adherence measures, the sample size, and the study design. It is argued that outcomes for the option "nonadherent" behavior should be described explicitly in the decision aid to inform patients about the costs and benefits of nonadherent behavior. Conclusions. A relation between decision aids and adherence is plausible in view of the psychological and medical literature. A systematic search showed that experimental evidence relating decision aids and adherence is inconclusive. Rigorous trials on this topic are worthwhile. Such trials should employ adequate sample sizes, multiple adherence measures, and a control arm delivering usual care. The decision aid should describe the option "being nonadherent" and its outcomes.

Straatman L.V.,Radboud University Nijmegen
The Journal of the Acoustical Society of America | Year: 2010

Cochlear implants are largely unable to encode voice pitch information, which hampers the perception of some prosodic cues, such as intonation. This study investigated whether children with a cochlear implant in one ear were better able to detect differences in intonation when a hearing aid was added in the other ear ("bimodal fitting"). Fourteen children with normal hearing and 19 children with bimodal fitting participated in two experiments. The first experiment assessed the just noticeable difference in F0, by presenting listeners with a naturally produced bisyllabic utterance with an artificially manipulated pitch accent. The second experiment assessed the ability to distinguish between questions and affirmations in Dutch words, again by using artificial manipulation of F0. For the implanted group, performance significantly improved in each experiment when the hearing aid was added. However, even with a hearing aid, the implanted group required exaggerated F0 excursions to perceive a pitch accent and to identify a question. These exaggerated excursions are close to the maximum excursions typically used by Dutch speakers. Nevertheless, the results of this study showed that compared to the implant only condition, bimodal fitting improved the perception of intonation.

Vrancken A.C.T.,Radboud University Nijmegen | Buma P.,Radboud University Nijmegen | Van Tienen T.G.,Radboud University Nijmegen
International Orthopaedics | Year: 2013

The number of meniscus-related operations continues to rise due to the ageing and more active population. Irreparable meniscal lesions generally require (partial) meniscectomy. Although a majority of the patients benefit from pain relief and functional improvement post-meniscectomy, some remain symptomatic. As an alternative to a meniscal allograft, which is only indicated for the severely damaged meniscus, most patients can nowadays be treated by implantation of a synthetic meniscal substitute. Currently three of these implants, two partial and one total replacement, are clinically available and several others are in the stage of preclinical testing. Grossly, two types of meniscal substitutes can be distinguished: porous, resorbable implants that stimulate tissue regeneration and solid, non-resorbable implants that permanently replace the whole meniscus. Although the implantation of a porous meniscus replacement generally seems promising and improves clinical outcome measures to some degree, their superiority to partial meniscectomy still needs to be proven. The evaluation of new prostheses being developed requires a wider focus than has been adopted so far. Upon selection of the appropriate materials, preclinical evaluation of such implants should comprise a combination of (in vitro) biomechanical and (in vivo) biological tests, while up to now the focus has mainly been on biological aspects. Obviously, well-defined randomised controlled trials are necessary to support clinical performance of new implants. Since the use of a meniscus replacement requires an additional costly implant and surgery compared to meniscectomy only, the clinical outcome of new products should be proven to surpass the results of the conventional therapies available. © 2012 Springer-Verlag Berlin Heidelberg.

Gevers T.J.G.,Radboud University Nijmegen | Drenth J.P.H.,Radboud University Nijmegen
Nature Reviews Gastroenterology and Hepatology | Year: 2013

Polycystic liver disease (PLD) is arbitrarily defined as a liver that contains >20 cysts. The condition is associated with two genetically distinct diseases: as a primary phenotype in isolated polycystic liver disease (PCLD) and as an extrarenal manifestation in autosomal dominant polycystic kidney disease (ADPKD). Processes involved in hepatic cystogenesis include ductal plate malformation with concomitant abnormal fluid secretion, altered cell-matrix interaction and cholangiocyte hyperproliferation. PLD is usually a benign disease, but can cause debilitating abdominal symptoms in some patients. The main risk factors for growth of liver cysts are female sex, exogenous oestrogen use and multiple pregnancies. Ultrasonography is very useful for achieving a correct diagnosis of a polycystic liver and to differentiate between ADPKD and PCLD. Current radiological and surgical therapies for symptomatic patients include aspiration-sclerotherapy, fenestration, segmental hepatic resection and liver transplantation. Medical therapies that interact with regulatory mechanisms controlling expansion and growth of liver cysts are under investigation. Somatostatin analogues are promising; several clinical trials have shown that these drugs can reduce the volume of polycystic livers. The purpose of this Review is to provide an update on the diagnosis and management of PLD with a focus on literature published in the past 4 years. © 2013 Macmillan Publishers Limited. All rights reserved.

Fallon S.J.,Radboud University Nijmegen | Cools R.,Radboud University Nijmegen
Journal of Cognitive Neuroscience | Year: 2014

Working memory and reward processing are often thought to be separate, unrelated processes. However, most daily activities involve integrating these two types of information, and the two processes rarely, if ever, occur in isolation. Here, we show that workingmemory and reward interact in a task-dependentmanner and that this task-dependent interaction involves modulation of the pFC by the ventral striatum. Specifically, BOLD signal during gains relative to losses in the ventral striatum and pFC was associated not only with enhanced distractor resistance but also with impairment in the ability to update working memory representations. Furthermore, the effect of reward on working memory was accompanied by differential coupling between the ventral striatum and ignore-related regions in the pFC. Together, these data demonstrate that reward-related signals modulate the balance between cognitive stability and cognitive flexibility by altering functional coupling between the ventral striatum and the pFC.  © 2014 Massachusetts Institute of Technology

Seyedmousavi S.,Radboud University Nijmegen
Expert review of anti-infective therapy | Year: 2013

Voriconazole and posaconazole are extended-spectrum triazoles recommended for treatment, prophylaxis and salvage therapy of Aspergillus diseases. Over the past decade many papers have emerged supporting the use of therapeutic drug monitoring (TDM) for azole antifungals. TDM is used to tailor the exposure of a specific drug to the individuals to optimize treatment response and minimize side effects. We reviewed the pharmacokinetics and pharmacodynamics (PK-PD) characteristics of voriconazole and posaconazole. We present the available evidence on target concentrations defining maximal efficacy and minimal toxicity. Finally we provide some practical recommendations how to best perform TDM in clinical practice.

Muradian R.,Radboud University Nijmegen | Walter M.,Autonomous University of Barcelona | Martinez-Alier J.,Autonomous University of Barcelona
Global Environmental Change | Year: 2012

This introductory paper to the special section of Global Environmental Change entitled "Global transformations, social metabolism and the dynamics of socio-environmental conflicts" argues that the emergence of new global economic centers is inducing a major expansion in the global social metabolism-the flows of energy and materials into the world economy -, a transformation in the systems for the extraction and provision of natur